Background : Gay men experience heterosexist harassment, rejection, and discrimination because of their sexual orientation, which leads to mental health problems, such as substance use. Due to anti-gay laws and regulations in Iran, which are based on fundamental interpretations of Islam, gay men are likely to experience more discrimination than in Western countries. Methods: We used the HHRDS to assess heterosexist harassment, rejection, and discrimination and the ASSIST 3.0 to measure substance use in N = 156 Iranian gay men. Results: Lifetime use was as follows: 64.1% for tobacco products, 36.5% for alcoholic beverages, 25.6% for cannabis, 8.3% for opioids, and 7.1% for sedatives or sleeping pills. All three HHRDS subscales were significantly associated with all substance use scales. In addition, when descriptively comparing HHRDS scores with those of US samples, Iranian gay men reported more discrimination. In a MANOVA, total discrimination strongly predicted tobacco and cannabis consumption, while total discrimination predicted alcohol, opioid, and sedative/sleeping pill use to a moderate degree. Conclusions: Substance use in Iranian gay men can be seen as a primary mental-health issue resulting from discrimination. It also likely reflects a maladaptive coping strategy related to these experiences. To improve Iran gay men’s mental health, structural and interpersonal discrimination should be eliminated and specialized psychological services should be established.