Understanding the dissolution mechanisms involved in calcium pyrophosphate dihydrate (CPPD) crystals may prove important for the development of therapy for CPPD arthropathy. We demonstrate that yeast pyrophosphatase effectively dissolved CPPD crystals in solutions. Maximum enzymatic dissolution of CPPD crystals was achieved at neutral pH and when the enzyme had access to the crystal surface. The enzymatic dissolution of CPPD crystals was highly dependent on ambient [Mg++] and [Ca++]. The stimulating effects of Mg++ on crystal dissolution in the presence of the enzyme is due to stimulation of pyrophosphatase activity and to enhanced direct release of pyrophosphate ions from the crystal surface. The inhibiting effect of Ca++ on crystal dissolution by the enzyme is mainly due to the suppression of pyrophosphatase activity.