The objective of this study was to identify risk factors for knee osteoarthritis (OA) development in a young to middle-aged population with sub-acute knee complaints. This, in order to define high risk patients who may benefit from early preventive or future disease modifying therapies. Knee OA development visible on radiographs and MR in 319 patients (mean age 41.5 years) 10 years after sub-acute knee complaints and subjective knee function (KOOS score) was studied. Associations between OA development and age, gender, activity level, BMI, meniscal or anterior cruciate ligament (ACL) lesions, OA in first-degree relatives and radiographic hand OA were determined using multivariable logistic regression analysis. OA on radiographs and MR in the TFC is associated with increased age (OR: 1.10, 95 % 1.04-1.16 and OR: 1.07, 95 % 1.02-1.13). TFC OA on radiographs only is associated with ACL and/or meniscal lesions (OR: 5.01, 95 % 2.14-11.73), presence of hand OA (OR: 4.69, 95 % 1.35-16.32) and higher Tegner activity scores at baseline before the complaints (OR: 1.20, 95 % 1.01-1.43). The presence of OA in the TFC diagnosed only on MRI is associated with a family history of OA (OR: 2.44, 95 % 1.18-5.06) and a higher BMI (OR: 1.13, 95 % 1.04-1.23). OA in the PFC diagnosed on both radiographs and MR is associated with an increased age (OR: 1.06, 95 % 1.02-1.12 and OR: 1.05, 95 % 1.00-1.09). PFC OA diagnosed on radiographs only is associated with a higher BMI (OR: 1.12, 95 % 1.02-1.22). The presence of OA in the PFC diagnosed on MR only is associated with the presence of hand OA (OR: 3.39, 95 % 1.10-10.50). Compared to normal reference values, the study population had significantly lower KOOS scores in the different subscales. These results show that knee OA development in young to middle aged patients with a history of sub-acute knee complaints is associated with the presence of known risk factors for knee OA. OA is already visible on radiographs and MRI after 10 years. These high risk patients may benefit from adequate OA management early in life.