Objectives: Knee osteoarthritis (OA) is characterized by its heterogeneity, with large differences in clinical characteristics between patients. Therefore, a stratified approach to exercise therapy, whereby patients are allocated to homogeneous subgroups and receive a stratified, subgroup-specific intervention, can be expected to optimize current clinical effects. Recently, we developed and pilot tested a model of stratified exercise therapy based on clinically relevant subgroups of knee OA patients that we previously identified. Based on the promising results, it is timely to evaluate the (cost-)effectiveness of stratified exercise therapy compared with usual, “nonstratified” exercise therapy. Methods: A pragmatic cluster randomized controlled trial including economic and process evaluation, comparing stratified exercise therapy with usual care by physical therapists (PTs) in primary care, in a total of 408 patients with clinically diagnosed knee OA. Eligible physical therapy practices are randomized in a 1:2 ratio to provide the experimental (in 204 patients) or control intervention (in 204 patients), respectively. The experimental intervention is a model of stratified exercise therapy consisting of (a) a stratification algorithm that allocates patients to a “high muscle strength subgroup,” “low muscle strength subgroup,” or “obesity subgroup” and (b) subgroup-specific, protocolized exercise therapy (with an additional dietary intervention from a dietician for the obesity subgroup only). The control intervention will be usual best practice by PTs (i.e., nonstratified exercise therapy). Our primary outcome measures are knee pain severity (Numeric Rating Scale) and physical functioning (Knee Injury and Osteoarthritis Outcome Score subscale daily living). Measurements will be performed at baseline, 3-month (primary endpoint), 6-month (questionnaires only), and 12-month follow-up, with an additional cost questionnaire at 9 months. Intention-to-treat, multilevel, regression analysis comparing stratified versus usual care will be performed. Conclusion: This study will demonstrate whether stratified care provided by primary care PTs is effective and cost-effective compared with usual best practice from PTs.