Natsume is a extremely intelligent, to the point of being considered a genius, and despite this, ditches class frequently. Hated and feared by a lot of students at the academy because of his dangerous Alice and cold attitude. Due to the isolation he feels from most of his classmates and hatred many student feel about him he is often bullied even though he comes to ignore it, although the class he is a part of holds him in very high regard and often follows his orders. He is thoroughly unhappy with the school and is always suspicious of the intentions of adults because he believes that they use their power over the younger students to hurt and abuse. He is paired up as Mikan's partner in class by the their mostly-absent class teacher, Narumi. Although at first he rebels strongly against this duty, he later accepts it and begins to enjoy Mikan's company, along with the company of his classmates and finds himself getting friendlier as the series progresses, although he never quite loses his dangerous edge and temper. He possesses the fire Alice. It is revealed early on that since Natsume has such a powerful Alice, it causes a lot of stress on his body to use and shortens his lifespan immensely.

Mikan is the protagonist of the story. She is a cute, energetic, good-natured girl, but her clumsiness lands her into trouble. She is a very up-an-at-it and athletic person, much to annoyance of her down-to-earth friend, Hotaru. She used to live with her grandfather in the country. She was shocked to hear that Hotaru was moving back to the city to go to an academy for young 'geniuses' like her. When she heard rumors that students were like slaves in Alice Academy (which she felt was a possibility, since they gave money to parents for sending their children to the school), Mikan left her grandfather and her home to go after Hotaru by herself. She was then accepted to Alice Academy by Narumi-sensei and could attend Alice Academy with Hotaru and many other children with extraordinary powers. Her Alice is Nullification, which can resist the effect of Pheromone type Alices and completely negate the powers of other Alices in close proximity to her. She also possesses the Stealing Alice, which she inherited from her mother. Both of her Alices are very rare and special. She once belonged to the Special Ability Class. Later, she gets transferred to the Dangerous Ability Class, and becomes the Elementary Principal's precious favorite. She is currently a Single Star, but it's most likely changed to Special Star due to the fact she is highly favored by the principal. Throughout the story, she has a lot of effect on Natsume and Ruka, who have both started to fall in love with her. As the story progresses she becomes liked and admired by a lot of the people that used to feel uneasy about her Alice. Even her relationship with Hotaru grows stronger. Her name means "Mandarin Orange" in Japanese.

Hotaru is an extremely intelligent and rational girl. She is considered to be a geek and more than a little strange because of her aloofness. Like Natsume, she is usually poker-faced, but possesses some humor in her. She may treat Mikan unkindly most of the time, but it is apparent that she deeply cares for her. Somehow, she likes to bully people she likes. Hotaru is Mikan's best friend and the main reason why Mikan came to the academy. She and Mikan have what may seem to be a doubtful and strange relationship. Hotaru comes off as cold, quiet, geeky, and bad-mouthed but calm. Her "stupid" points are her tendency of being a "pig" when it comes to food and her greedy side, this happens in a comical manner. Her Alice is Invention, which allows her to create unique and strange inventions. She belongs to the Technical Class. She is currently a Triple Star. Her name "蛍 - Hotaru" means "Firefly".

Ruka is Natsume's childhood friend and often referred by Mikan throughout the story as "Ruka-pyon". He has a gentle and pleasant personality that balances out that of Natsume's. Even though he tries to hide his feelings for Mikan Sakura, the grown-ups already know about it and even teased Ruka many times by the Watching Over Ruka Group. He always carries around a rabbit and has a way with animals, they seem to attract to him. He is also the main target of Hotaru, who loves clicking funny pictures of him and selling them. He belongs to the Somatic class. He is a Triple Star student like Hotaru.