Cellular immunity to rabbit types I, II, and III collagen was detected after both partial medial meniscectomy and sham operation in rabbits when an in vitro 3H-thymidine incorporation assay was used. The blastogenic responses were commonly directed towards peptides derived from collagens by cyanogen bromide cleavage used to mimic proteinase degradation products. The responses to type III collagen peptides were by far the strongest and were seen in most rabbits that were operated on. We suggest that the responses to types I and II collagen were caused by a cross-reaction with type III collagen peptides. This conclusion was supported by the observation that spleen cells from rabbits directly immunized with homologous type III collagen peptides in Freund's complete adjuvant responded strongly to the immunizing peptides and also cross-reacted with types I and II collagen peptides. Immunity to cartilage proteoglycans was observed primarily in rabbits that had undergone meniscectomy and had severe cartilage degeneration. These results indicated that immunity to collagens will develop merely as a result of joint surgery, whereas immunity to proteoglycans is largely dependent upon an osteoarthritic lesion.