Perception of loneliness has been identified as the strongest predictor of health-related quality of life assessed with the Assessment of Quality of Life-4D in people with psychotic disorders. We aimed to establish contributors to perceived loneliness, and ascertain the mediating role of loneliness in the relationship between identified contributors to loneliness and other known predictors of health-related quality of life with health-related quality of life. Data for 1642 people collected as part of the 2010 Australian National Survey of Psychosis were analysed. Health-related quality of life was assessed using the Assessment of Quality of Life-4D, and loneliness through a single-item five-level categorical variable. To identify independent contributors to loneliness, a statistical model was constructed with reference to a theoretical model comprising 23 variables. A predictive model with health-related quality of life as the dependent variable was then developed and tested to assess the mediating role of loneliness. Nine contributors to loneliness were found (social dysfunction, experienced stigma, contact with friends, diagnosis, depressive symptoms, anxiety, mental health service utilisation, arthritis and traumatic events in childhood), with social dysfunction the strongest. In the prediction of health-related quality of life, all contributors to loneliness were partially mediated through loneliness (except service utilisation) as were negative symptoms and use of psychotropic/anticholinergic medications. Assuming a plausible causal model of mediation, loneliness was found to have direct and indirect effects on health-related quality of life in people with psychotic disorders. Findings add impetus to efforts to develop and trial strategies aimed at reducing loneliness in this population, and, in turn, improving their health-related quality of life.