Objective: Quadriceps weakness has been reported with incident but not progressive knee osteoarthritis (OA) in longitudinal studies. This study examined the relationship between quadriceps strength and worsening of knee joint space narrowing (JSN) over 30 months. Methods: Longitudinal, observational study of adults aged 50-79 years with OARSI JSN score <3 at baseline. Baseline measures included bilateral weight-bearing fixed flexion radiographs, isokinetic concentric quadriceps and hamstring strength, height and weight, and physical activity. Hamstring:quadriceps (H:Q) strength ratios also were evaluated. Worsening was defined as an increase in JSN score in the tibiofemoral and/or patellofemoral compartments on 30-month radiographs or total knee replacement. Knee-based analyses used generalized estimating equations, stratified by sex, to assess relationships between strength and knee JSN while controlling for covariance between knees within subjects as well as age, body mass index (BMI), history of knee injury and/or surgery, physical activity level and alignment. Results: 3856 knees (2254 females and 1602 males) with JSN score <3 at baseline and no missing follow-up data were included. Mean ± SD age was 62.2 ± 7.7 in women and 61.6 ± 8.1 in men. Women in the lowest tertile of quadriceps strength had an increased risk of whole knee JSN (OR=1.66, 95% CI =1.26, 2.19) and tibiofemoral JSN (OR=1.69, 95% CI=1.26, 2.28). However, no associations were found between strength and JSN in men or H:Q < 0.6 and JSN in men or women. Conclusions: In women but not in men, quadriceps weakness was associated with increased risk for tibiofemoral and whole knee JSN. © 2010 Osteoarthritis Research Society International.