The purposes of this study were to document the histological changes present in the tibial plateaus 12 weeks after complete medial meniscectomy in dogs and to determine if synovial lavage fluid biomarker levels are predictive of the severity of joint damage. Twelve adult dogs underwent complete unilateral medial meniscectomy and synovial lavage fluid biomarker levels, including cartilage oligomeric matrix protein (COMP), keratan sulfate (5D4). 3B3(-), and 3B3(+), were measured serially at 4-week intervals. The dogs were euthanized 12 weeks after surgery and each medial and lateral tibial plateau from the meniscectomized and contralateral knees was graded histologically. Histological data were analyzed using principal components analysis, which resulted in 4 factors that explained 70% of the variation in the data. Factor 2 (weighted most heavily by subchondral bone thickness) and Factor 3 (representative of articular cartilage damage) were significantly affected by compartmental site (P < 0.01 for both). Both of these factors were highest in the medial tibial plateau of the meniscectomized knee, and Factor 3 was significantly higher in this site than in the medial tibial plateau of the contralateral knee (P < 0.01). Peak levels of all 4 synovial lavage fluid biomarkers occurred at 4 weeks post-meniscectomy and 4-week minus baseline levels of all biomarkers were significantly correlated with the Factor 3 scores. This study demonstrates that significant articular cartilage damage occurs relatively quickly following complete medial meniscectomy in dogs and establishes the content and criterion validity for these synovial fluid lavage biomarkers in canine meniscectomy as surrogate measures of articular cartilage damage.