Purpose: The observed heterogeneity in osteoarthritis with respect to e.g. risk factors, symptoms, affected joints and progression, gave rise to the idea that OA is in fact a collection of distinct disease subtypes. In this study we explored whether two etiologically distinct subtypes of knee OA with equal radiological OA severity, differ in osteoarthritis features as seen on MRI. The subtypes comprised a group with metabolic syndrome and a group of lean physically active subjects. Methods: From all subjects of the Osteoarthritis Initiative (OAI) incidence subcohort, who had a KL score ≥ 2 in at least one knee at 48 months follow-up, we included two groups of 50 subjects, matched for KL score. To be included in the metabolic syndrome group subjects needed to have a BMI > 30 kg/m2 or abdominal circumference >94 cm for males or >80 cm for females. Further, 2 out of 3 of the following criteria needed to be present: hypertension (RR > 130/85 mmHg or use of hypertension medication), insulin resistance (reported high blood sugar or use of diabetic medication) or dyslipidemia (use of lipid lowering medication). Inclusion criteria for the physically active lean group were a BMI < 25 kg/m2 and a Physical activity scale for the elderly (PASE) score ≥ 2, which indicates strenuous sport/recreation activities. MRI scans made at 48 month follow-up were requested for these subjects from the OAI database, and one randomly selected OA knee from each subject was scored using the MRI Osteoarthritis Knee Score (MOAKS). Results: The metabolic syndrome group consisted of 28 females and 22 males with an average age of 63.4 years while the physically active lean group consisted of 37 females and 13 males with an average age of 61.3 years. Scores for bone marrow lesions (BMLs), and cartilage damage were consistently higher in most of the knee compartments in the metabolic syndrome group, but only for females and only significant for cartilage damage. In the lateral tibia, however, scores for BMLs and cartilage damage were lower in the metabolic syndrome group, for both sexes. Osteophyte scores were higher for all compartments in the metabolic syndrome group, irrespective of sex, though these differences were only significant for a few compartments in females (see Fig.). Scores of meniscal tears and Hoffa synovitis were significantly higher in the physically active lean group while high prepatellar signal was more often seen in the metabolic syndrome group, especially in the females. Conclusions: Metabolic OA and OA related to physical activity showed clear differences in MRI OA features, depending on sex and knee compartment. Intriguing is the difference between men and women in the pattern in which cartilage damage and BMLs are distributed over the compartments (see Fig.). This is suggestive of differences in biomechanics of the knee between the sexes, which have been shown to underlie the higher prevalence of patello-femoral problems in women. The fact that metabolic syndrome is associated with worse scores in women but not in men might be attributed to differences in fat distribution. Fat in females is deposited mostly subcutaneously, while males have more visceral fat. The subcutaneous amount of fat is related to leptin levels, and interestingly, leptin levels have been shown to influence OA, especially in women. Another interesting finding is that osteophyte scores behave differently than scores for BMLs and cartilage damage, in that the distribution over the compartments is less pronounced, and that scores are higher in the metabolic syndrome group, for both sexes. This suggests that the etiological process for osteophyte development is at least partly independent from the processes that influence cartilage damage and BMLs. In conclusion, these results suggest that different etiological processes in knee OA do lead to differences in structural degradation, which is probably modulated by biomechanical loads in the different compartments of the knee.