According to the World Health Organization, 1 out of 200 people in the world was living with Human immunodeficiency virus (HIV)/Acquired immune deficiency syndrome (AIDS) in 2015 and four new HIV infections occurred each minute. A relationship between HIV infection and recreational drug use was evident from the very beginning of the HIV epidemic. Recreational drug use is more common in patients living with HIV/AIDS compared to others. Needle-sharing activities, psychological and cognitive consequences of the abused substances facilitate new infections. It is assumed that 1.650.000 individuals were infected with HIV out of 12.190.000 intravenous drug users in 158 countries in 2013. Cytochrome isoenzymes (i.e. CYP3A4, CYP2D6) are responsible from metabolism of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and chemokine receptor 5 inhibitors as well as recreational drugs. Recreational and antiretroviral drugs (ARV) may share the same metabolic pathways resulting in drug interactions. Drug interactions may occur because of pharmacodynamic and pharmacokinetic properties of the drugs. Induction of CYP3A4 (due to cocaine, tobacco, chronic alcohol use, etc.) may lead to decreased antiretroviral treatment (ART) effectiveness and increased risk of metabolites-related toxicity, however, inhibition of CYP3A4 (due to marijuana, acute alcohol use, etc.) may lead to increased side effects and drug toxicity. The feeling of moving away from reality and reduction of social pressure associated with recreational drugs mean all the world to the user. However, drug interaction risk makes it challenging for the physicians, when it is time for the selection of ARV. Therefore, physicians' awareness on the interaction of these drugs is very important. Interactions with recreational drugs should be considered when prescribing ART for these patients. Integrase inhibitors and nucleoside/nucleotide reverse transcriptase inhibitors are safe to use in these circumstances. In this paper, drug interactions between ARV and alcohol, benzodiazepines, opiates, cocaine, methamphetamine, ecstasy, lysergic acid diethylamide, ketamine, gamma hydroxylbutyrate, marihuana, and phencyclidine are reviewed.