OBJECTIVE: Homocysteine has been implicated in multiple diseases that involve changes in structural tissue. In vitro studies have found that it alters the structure of collagen cross-linking thus affecting stability and mineralization such as that occurring in bone tissue. In the present study we considered the possible relationship between plasma homocysteine levels and the development and progression of knee osteoarthritis (OA). METHODS: The study question was posed in 691 men and 966 women from the original and offspring cohorts of the Framingham Osteoarthritis Study. We divided individuals into three groups according to plasma homocysteine levels and compared their risk for the development of new and progression of existing OA. We adjusted for potential confounders including age, body mass index, weight change, and physical activity. RESULTS: In the crude analysis, men in the middle homocysteine tertile were found to be at a greater risk than men in the lowest tertile for incident OA [odds ratios of 1.9 (1.1-3.5)]. This result persisted after adjusting for covariates [odds: 2.0, (1.1-3.8)]. No significant correlation was seen in women for the development of OA. In the evaluation of progression no significant trends were seen for both men and women. CONCLUSIONS: Although cellular and molecular studies of homocysteine-related pathophysiology suggest a possible correlation between plasma homocysteine levels and OA, the present clinical study did not conclusively demonstrate such an association. However, further research is needed to explore the role of homocysteine in specific aspects of OA etiopathogenesis.