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Objectives: Osteoarthritis (OA) of the foot-ankle complex is understudied. Understanding determinants of pain and activity limitations is necessary to improve management of foot OA. The aim of the present study was to investigate demographic, foot-specific and comorbidity-related factors associated with pain and activity limitations in patients with foot OA., Methods: This exploratory cross-sectional study included 75 patients with OA of the foot and/or ankle joints. Demographic and clinical data were collected with questionnaires and by clinical examination. The outcome variables of pain and activity limitations were measured using the Foot Function Index (FFI). Potential determinants were categorized into demographic factors (e.g., age, sex), foot-specific factors (e.g., plantar pressure and gait parameters), and comorbidity-related factors (e.g., type and amount of comorbid diseases). Multivariable regression analyses with backward selection (p-out≥0.05) were performed in two steps, leading to a final model., Results: Of all potential determinants, nine factors were selected in the first step. Five of these factors were retained in the second step (final model): female sex, pain located in the hindfoot, higher body mass index (BMI), neurological comorbidity, and Hospital Anxiety and Depression Scale (HADS) score were positively associated with the FFI score. The explained variance ( R 2 ) for the final model was 0.580 (adjusted R 2  ​= ​0.549)., Conclusion: Female sex, pain located in the hindfoot, higher BMI, neurological comorbidity and greater psychological distress were independently associated with a higher level of foot-related pain and activity limitations. By addressing these factors in the management of foot OA, pain and activity limitations may be reduced., Competing Interests: The authors have no competing interests to declare., (© 2021 The Authors.)