Synovial, meniscal, articular cartilage, and other connective tissue from fifty-seven patients who had calcium pyrophosphate dihydrate crystal-deposition disease was examined by light microscopy, electron microscopy, and electron-probe microanalysis. Safranin O-positive hypertrophic chondrocytes that contained proteoglycans were observed in the tissues of each patient. Microcrystals that were suggestive of early precipitation of crystals were found in the degenerating matrix surrounding hypertrophic chondrocytes. The matrix contained electron-dense amorphous material, including proteoglycans and debris of cellular components. The microcrystals were often seen in contact with degenerating collagen fibers. There was never any histological evidence of formation of crystal in the areas that had no hypertrophic chondrocytes. Chondrocytes of this kind, surrounded by characteristic degenerating matrix, were never observed in the articular tissue from sixty-one patients who had only osteoarthritis. On the basis of our results, we speculate that electron-dense amorphous material containing proteoglycans and debris of cellular components, and the degenerating collagen fibers that were seen around the hypertrophic chondrocytes, may play important roles in the formation of calcium pyrophosphate dihydrate crystals.