Learning about possible factors influencing, positively or negatively, the Quality of Life (QoL) of patients with psychosis is an important task for both, research and treatment. The study examined the association of illness course with QoL in a sample of Mexican patients with psychosis. It was hypothesized that illness perception would mediate the relation of illness course to QoL. Sixty-one (56 % female) patients were interviewed and assessed for illness course (relapses, residual symptoms, and diagnosis), QoL, and illness perception. Mediation analyses (simple and multiple) with bootstrapping procedures were applied, including residual symptoms as the predictor of QoL, and illness perception dimensions as candidate mediators. Residual symptoms, rather than a relapsing course or a diagnosis of schizophrenia, have a diminishing effect in the subjective QoL. This effect is fully mediated by illness perception, particularly by the cognitive and the emotional representations. Results underscore the importance that patients’ beliefs have on their perceived QoL, encouraging further research and development of interventions targeting illness perceptions.