BACKGROUND: Large variations in pain and function are seen over time in subjects at risk for and with radiographic knee osteoarthritis (OA). We hypothesized that this variation may be related not only to knee OA but also to patient characteristics. The objective of this study was to investigate the influence of age, gender, and body mass index (BMI) on clinically relevant change in pain and function over two years in subjects at high risk for or with knee OA. METHODS: We assessed 143 individuals (16% women, mean age 50 years [range 27-83]) twice; 14 and 16 years after isolated meniscectomy. Subjects completed one disease-specific questionnaire, the Knee injury and Osteoarthritis Outcome Score (KOOS) and one generic measure, the SF-36. Individuals with a BMI between 25 and 29.9 were considered overweight, while individuals with a BMI of 30 or more were considered obese. RESULTS: Subjects aged 46-56 (the middle tertile) were more likely to change (> or =10 points on a 0-100 scale) in the KOOS subscale Activities of Daily Living (ADL) than younger subjects (odds ratio [OR] 4.5, 95% confidence interval [95% CI] 1.5-13.0). Essentially the same result was obtained after adjusting for baseline values. Overweight or obesity was a risk factor for clinically relevant change for knee pain (OR 2.4, 95% CI 1.0-5.8, OR 4.0, 95% CI 1.2-13.6) and obesity for change in ADL (OR 4.3, 95% CI 1.2-15.4). The results did not remain significant when adjusted for the respective baseline value. Being symptomatic was strongly associated with increased variation in pain and function while presence or absence of radiographic changes did not influence change over two years in this cohort. CONCLUSION: In a population highly enriched in early-stage and established knee OA, symptomatic, middle-aged, and overweight or obese subjects were more likely to vary in their knee function and pain over two years. The natural course of knee pain and function may be associated with subject characteristics such as age and BMI.