Introduction and purpose The purpose was to analyze socioeconomic and clinical factors of psychosocial functioning and self-perception in relation to health-related quality of life (HRQOL) in people with severe mental health illness (SMI) by gender. Materials and method A cross-sectional study was conducted on a sample of 133 women and 90 men. Recorded variables: HRQOL, SF-36 Physical Component Scores (PCS) and Mental Component Scores (MCS); sociodemographic and clinical data on psychosocial and self-perception functioning. Correlational studies using raw and adjusted linear regression models to evaluate the factors associated with HRQOL by obtaining coefficients, p-values and respective confidence intervals. Results The mean PCS for women and men was 44.6 and 49.0 (p = 0.004) and 36.4 and 37.5 (p = 0.575), respectively for MCS. The factors associated with PCS in women were age,-0.2 (-0.4:0); in work, 4.2(0.3:8.2); with an income higher than 700 euros/month, 4.4(1:7.7). In men, these factors were education level, 6.1(0.4:11.7); belief that they would not need help in the future, 4.6(0.1:9.2) and a higher need for psychosocial services,-6.6(-11.1:-2). Factors associated with MCS in women were,