There is limited understanding of how comorbid health conditions affect osteoarthritis (OA)-related outcomes. This study examined associations of different comorbidity measures with baseline OA-related patient-reported outcomes (PROs) among patients with hip and knee OA. Data were from patients (N = 300, 9 % female, mean age = 61.1; SD = 9.2) enrolled in a randomized control trial at the Durham Veterans Affairs Medical Center. Separate multivariable regression models, adjusted for demographic and clinical characteristics, examined the association of each comorbidity measure with baseline PROs: pain, physical function, depressive symptoms, fatigue, and insomnia. Comorbidity measures included the Self-Administered Comorbidity Questionnaire (SACQ), conditions reported as activity-limiting (SACQ-AL), and indicators of depression, diabetes, hypertension, and back pain. Mean (SD) numbers of comorbid conditions and activity-limiting conditions were 3.4 (1.8) and 1.6 (1.4), respectively. Comorbidity scores (SACQ overall and SACQ-AL) and individual comorbidity conditions were each associated with worse OA-related PROs adjusting for demographic and clinical factors. Worse SACQ overall and SACQ-AL scores were associated with worse mean scores for pain, depressive symptoms, fatigue, and insomnia (p values <0.01). Additionally, increasing SACQ-AL scores were associated with worse mean scores for function (p < 0.01). Depression was associated with worse pain (p = 0.03), fatigue, and insomnia (p values <0.01). Diabetes was associated with worse fatigue (p = 0.01), depressive symptoms (p = 0.02), and insomnia (p = 0.03). Back pain was associated with worse pain scores (p = 0.02). Results provide evidence that comorbidity burden, particularly activity-limiting conditions, is associated with worse OA-related PROs. Interventions for patients with OA need to address comorbid conditions and their impact on key outcomes.