Objectives: Understanding patterns of quality of life in people who inject drugs (PWID) can help healthcare providers plan and manage their health problems in a more focused manner. Therefore, the current study aimed to identify patterns of health-related quality of life in PWID in southeast Iran. Methods: This cross-sectional study was conducted in southeast Iran on men who had injected drugs at least once during the last year. We used convenience sampling in 2 drop-in centers and venue-based sampling at 85 venues. Demographic characteristics, high-risk behaviors, and health-related quality of life were evaluated using the 5-level EQ-5D version (EQ-5D-5L) questionnaire. Latent profile analysis was used to identify patterns of quality of life. Results: This study enrolled 398 PWID, who had a mean age of 34.1±11.4 years. About 47.9% reported a prison history in the last 10 years, 59.2% had injected drugs in the last month, and 31.6% had a history of sharing syringes. About 46.3% reported having 2 or more sexual partners in the last 6 months, and 14.7% had a history of sex with men. Out of the 5 EQ-5D-5L profiles, the fifth profile had the most people (36.6%). Most variations in quality of life were related to pain and discomfort. Conclusions We showed that the pain and discomfort dimension of EQ-5D-5L had more variation in PWID. This finding will be useful for allocating appropriate interventions and resources to promote health-related quality of life in this population.