Objective: To evaluate the influence of happiness therapy intervention on the medication compliance and quality of life of acquired immune deficiency syndrome (AIDS) patients after discharge. Methods: A total of 106 adult AIDS patients discharged from hospital from July 2016 to July 2017 were randomly divided into control group (52 cases), observation group (54 cases). The control group was given routine health education and instruction, and three times of happiness therapy intervention were performed during the hospitalization. The observation group increased the number of happiness therapy intervention after discharge according to the patient′s medication compliance. The medication compliance scale and quality of life scale were used to evaluate the compliance rate and quality of life of patients in 2 groups at discharge, 3 months after discharge, 6 months after discharge, and 12 months after discharge. Results: There was no significant difference in medication compliance and quality of life at discharge and 3 months after discharge between the two groups (P>0.05). At 6 months and 12 months after discharge, the compliance rate and quality of life scores in the observation group was 90.74%(49/54), 88.89%(46/54) and (69.62 ± 5.82) points, (68.76 ± 5.63) points, respectively, 61.54% (32/52), 59.62% (31/52) and (52.12 ± 4.30) points, (52.05 ± 4.25) points in the control group, the difference was statistically significant (χ²=9.684, 9.035, t=8.638, 8.963, P<0.01). Conclusions The happiness therapy intervention during hospitalization can effectively improve the medication compliance and quality of life of AIDS patients. After the discharge, the happiness therapy intervention can provide the patients with long-term nursing programs, which can improve the adherence and quality of life of AIDS patients compared with the control group Have a better long-term effect.