Background: Drug abuse is the most problematic issue in many countries including Iran. Prevention, treatment and demand reduction programs of drug abuse have the highest priorities. In 2004, Iran's ministry of health and medical education (MOME) integrated prevention and treatment substance use and human immunodeficiency virus infection/acquired immune deficiency syndrome (HIV/AIDS) programs in the rural primary health care (PHC) system. Objectives: The aim of the present study was to evaluate the integration program of prevention and treatment of substance use and HIV/AIDS in the rural primary health care (PHC) system of Iran. Patients and Methods: This was a cross sectional descriptive/qualitative study about supervision, assessment and monitoring by mental health experts team during year 2009. Data was collected mostly from an expert panel, which monitored the program accurately. Results: The findings showed that the program was used in 380 health houses in 10 cities of Iran. The total number of inhabitants covered by the program were 5555258, and 8245 of them were substance abusers. The cases were registered and their data were reported by the managers. The function of health houses, health centers, and district health centers were assessed by considering the number of cases. The centers provided care services, interventions and harm reduction activities, and they referred some cases to specialists or other higher-level professional centers. Many educated experts including Behvarzes, multipurpose health workers, primary health personnel, educated general physicians (GPs) and family physicians (GFs) had worked actively in rural health centers. Furthermore, at district level, executive groups followed up cases were referred by (GFs). Conclusions: Integrating program of prevention and treatment of substance use and HIV/AIDS in PHC system of Iran has positive outcomes. It is one of the most effective ways in this domain. It has a coherent structure, and a high potential in the introducing of PHC services to the community. The program has important impacts on the provision of health services and representation of mental health in rural areas. It seems that the program successes in the most of its goals, and can be continued and enhanced with some changes and reforms in the country.