Objective: To determine whether quadriceps strength is associated with tibiofemoral osteoarthritis progression in persons with knee osteoarthritis. The association was examined particularly in malaligned knees and high-laxity knees. Design: Cohort study. Setting: Academic medical center in Chicago, Illinois. Participants: Participants for a natural history study (Mechanical Factors in Arthritis of the Knee) were recruited through periodicals, organizations, and medical center referrals. Inclusion criteria were osteophyte presence in 1 or both knees and difficulty with ≥2 items in the Western Ontario and McMaster University osteoarthritis index physical function scale. Exclusion criteria were corticosteroid injection within 3 months, inflammatory arthritis, comorbidity in the lower limb, and replacement or planned replacement of the arthritic knee(s). Of 237 participants, 230 were followed for 18 months, and 171 (mean age, 64 years; 74% women) who did not have advanced osteoarthritis at baseline (Kellgren and Lawrence grade 4) were included in the analysis (328 knees). Assessment of risk factors: Baseline measurements were obtained for both knees. Isokinetic quadriceps strength (maximal torque during movement) was assessed by means of a computer-driven isokinetic dynamometer. Alignment was measured on a single anterior radiograph of both lower extremities. A knee was considered malaligned if the angle of the intersection of the line between the centers of the femoral head and inter-condylar notch and the line between the centers of the ankle talus and tibial spines was 5° or more. High varus-valgus laxity (the sum of varus and valgus rotation for each knee measured at the foot) was defined as knees in the highest tertile (≥5.75°). Main outcome measures: The main outcome measure was tibiofemoral osteoarthritis progression (an increase in the grade of joint space narrowing) determined radiographically at baseline and 18 months. Main results: The predicted probability of arthritis progression, after adjustment for baseline age, body mass index, disease severity, and physical activity, was slightly greater in knees with greater quadriceps strength (>47.3 ft-lb) compared with lesser quadriceps strength (0.153 vs. 0.098; P = 0.09). In logistic regression, strength was associated with an increase in predicted probability of disease progression in malaligned knees (n = 78; high strength, 0.406. vs. low strength, 0.187; P = 0.03), but not in neutrally aligned knees (n = 250; P > 0.2). High strength in the knees with high laxity (≥5.75°; n = 110) and in knees with the greatest laxity (≥6.75°; n = 70) was associated with a greater probability of arthritis progression (P = 0.05 and P = 0.003, respectively). Conclusions: Quadriceps strength was not found to be beneficial in reducing the progression of tibiofemoral knee osteoarthritis in older adults. Quadriceps strength was predictive of more severe arthritis progression in malaligned knees and in knees with high laxity.