The sequential histopathologic alterations in femorotibial joints of partial meniscectomized male and female guinea pigs were evaluated at 1, 2, 3, 6, and 12 weeks post-surgery. Foci of moderate to severe cartilage degeneration were present in the medial tibial plateau and femoral condyle of the operated leg by 1 week post-surgery. At 2 weeks post-surgery, the cartilage degeneration in the operated legs was more extensive and there was evidence of early chondrophyte formation on the medial side of either the femur or tibia in three animals. Changes were progressively more severe at 3, 6, and 12 weeks. Focal areas of minimal to mild cartilage degeneration were in the medial tibial plateau of the contralateral nonoperated leg in some animals at 3 weeks post-surgery and in all animals at 12 weeks post-surgery. Changes in the contralateral leg of meniscectomized guinea pigs have not been described previously. Since cartilage degeneration was often severe by 1 week post-surgery, the model has limited utility for testing agents designed to modify the degenerative process in the operated leg. Milder, more slowly progressive lesions in the contralateral leg may be amenable to therapeutic intervention.