Background: In the bio-psycho-social model of health, the role of contextual factors, either environmental or personal, is recognised. Objective: To assess the impact of a number of contextual factors on self-reported disease-specific and generic health-related quality of life in patients with ankylosing spondylitis (AS). Methods: 522 patients with AS from Canada and Australia completed a postal questionnaire including sociodemographic variables, disease activity (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)) function (Bath Ankylosing Spondylitis Functional Index (BASFI)) health-related quality of life (ASQoL and EQ-5D) and Rheumatoid Attitudes Index Helplessness Subscale. The contribution of contextual factors (nationality, ethnicity, marital status, education, employment and helplessness) in addition to functioning and disability (BASDAI and BASFI) to health-related quality of life was analysed using multivariate regression analyses. Interactions between contextual variables were explored. Results: Contextual factors explained 37% and 47% of the variance in EQ-5D and ASQoL, respectively. Helplessness and employment were the most important contextual factors. Their role was independent of the strong effect of disease activity (BASDAI) and functional limitations (BASFI). When ASQoL was the outcome, an interaction was seen between employment and education and when EQ-5D was the outcome, an interaction was seen between helplessness and education. Conclusions: Of the contextual factors explored in this study, helplessness and employment had an important and independent contribution to health-related quality of life. In patients with lower education, the effect of not being employed on ASQoL and the effect of helplessness on EQ-5D were stronger. Contextual factors, especially helplessness and employment, should receive more attention when interpreting data on health-related quality of life.