Purpose/Objective: The International Classification of Functioning, Disability and Health (ICF) framework was used to investigate person–environment contextual factors, mental functioning, activity limitations, and participation as predictors of quality of life (QoL) in adults with severe mental illness (SMI). Research Method/Design: A quantitative descriptive design using multiple regression and correlational analyses was used. One hundred ninety-four individuals with SMI from 4 community-based mental health agencies in 2 states from Southern and Midwestern regions of the United States participated in the study. The criterion variable was QoL. Predictor variables comprised the ICF constructs: (a) demographics, (b) personal factors, (c) environmental factors, (d) mental functioning, (e) activity limitations, and (f) participation. Results: A majority of participants were White (60.3%) and not employed (59.8%). Half of them received Social Security Disability Income and/or Supplemental Security Income (50.0%). Correlations between QoL and the predictor variables ranged from small to large (r = .01 to .63, respectively). The final regression model accounted for 58% of the variance in QoL. After controlling for other factors, social competency, social support, societal stigma, psychological distress, cognitive dysfunction, activity limitations, and participation were found to be significant predictors of QoL in adults with SMI. Conclusions/Implications: The study supports the use of the ICF to predict QoL for adults with SMI. Evidence-based treatments focused on increasing social competence, social support, and participation should be developed to promote rehabilitation outcomes and overall QoL.