Self-administration provides insights into neurotransmitter systems (especially dopamine), and brain regions involved in the reward process and how they are altered by drug use. Self-administration procedures in experimental animals are one of the most reliable predictors for evaluating drug abuse potential. We built the mouse vapor self-administration model. We measured reinforcement of cocaine in vapor self-administration for mice. The 50, 100 mg/mL cocaine group and vehicle of mice stably self-administered on fixed ratio (FR) 1 or 2 schedule for 1 h/day sessions. The vapor delivery number of cocaine group were significantly increased compare with vehicle group in each session. There was significantly difference for average vapor delivery number between vehicle, 50, and 100 mg/mL cocaine group in male and female mice. LC-MS/MS results suggested that the cocaine consumption of male mouse was 0.22 mg and cocaine consumption of female mice was 0.06 mg. It suggested that cocaine vapor had a higher reinforcing effect in mice. The male mice have higher cocaine consumption than female mice. The mouse vapor self-administration can make a significant contribution to the drug reinforcement evaluation.