Introduction. Pain related to knee osteoarthritis (OA) is a complex phenomenon that cannot be fully explained by radiographic disease severity. We hypothesized that pain phenotypes are likely to be derived from a confluence of factors across multiple domains: knee OA pathology, psychology, and neurophysiological pain processing. The purpose of this study was to identify distinct phenotypes of knee OA, using measures from the proposed domains. Methods. Data from 3494 subjects participating in the Osteoarthritis Initiative (OAI) study was analyzed. Variables analyzed included: radiographic OA severity (Kellgren-Lawrence grade), isometric quadriceps strength, Body Mass Index (BMI), comorbidities, CES-D Depression subscale score, Coping Strategies Questionnaire Catastrophizing subscale score, number of pain sites, and knee tenderness on physical examination. Variables used for comparison across classes included pain severity, WOMAC disability score, sex and age. Latent Class Analysis was performed. Model solutions were evaluated using the Bayesian Information Criterion. One-way ANOVAs and post hoc least significance difference tests were used for comparison of classes. Results. A four-class model was identified. Class 1 (57% of study population) had lesser radiographic OA, little psychological involvement, greater strength, and less pain sensitivity. Class 2 (28%) had higher rates of knee joint tenderness. Class 3 (10%) had greater psychological distress and more bodily pain sites. Class 4 (4%) had more comorbidities. Additionally, Class 1 was the youngest, had the lowest disability, and least pain. Class 4 was the oldest. Class 2 had a higher proportion of females. Class 3 had the worst disability and most pain. Conclusions. Four distinct pain phenotypes for knee OA were identified. Psychological factors, knee tenderness, and comorbidities appear to be important in defining phenotypes of OA-related pain. Therapies in knee OA should take a multicomponent approach, recognizing the factors most relevant to an individual's experience of pain