Purpose Drug addiction and psychiatric disorders are frequently concomitant; however, few studies have investigated the impact of psychiatric disorders other than substance use disorder (SUD) on health-related quality of life (HRQoL) in drug users not in treatment. We studied the association of psychiatric disorders other than SUD with HRQoL in a street-recruited sample of cocaine and/or heroin users. Methods It is a cross-sectional study involving 287 young users of cocaine and/ or heroin in Barcelona, Spain. HRQoL was assessed with the Nottingham health profile (NHP). Patterns of drug use and mental disorders were assessed using the Spanish version of the psychiatric research interview for substance and mental disorders IV, and degree of dependence through the severity of dependence scale (SDS). The association of mental disorders with HRQoL was assessed through a Tobit regression analysis. Results The overall NHP score was 23.9 (SD = 20.5, range 0-91.7). Sixty-one percent of the sample had two or more SUDs; 22 % had at least one non-SUD Axis I disorder (anxiety, mood, psychotic, or eating disorder); and 27.2 % had a borderline personality disorder (BPD) and/or antisocial personality disorder. Variables negatively associated with the global NHP score were psychosis [transformed beta coefficient: 15.23; 95 % confidence interval [CI] 4.48-25.97], BPD (9.55; 95 % CI 2.95-16.15), severity of dependence (8.12; 95 % CI 3.37-12.87), having two or more SUDs (for two or three SUDs: 6.83; 95 % CI 2.08-11.59) (>3 SUDs: 7.70; 95 % CI 1.72-13.68) and the intravenous use of some substance (10.20; 95 % CI 6.00-14.40). Conclusion HRQoL among street-recruited illegal substance users was impaired, particularly among those with psychiatric comorbidity, psychosis, and BPD being especially relevant.