Cryptosporidia from natural cryptosporidiosis in guinea pigs were experimentally transmitted to both adult and juvenile guinea pigs. Cryptosporidia were associated with the villi of the ileum, jejunum, and duodenum. Both juveniles and adults were equally susceptible to cryptosporidia, as determined by decreases in villus height, increases in crypt depth, and decreases in villus height/crypt depth ratios, when compared with uninoculated animals. When multiple paired comparisons were made between 2 and 10 days postinoculation, there were significant decreases in villus height/crypt depth ratios with time. A dose study showed that 6-week-old guinea pigs were all infected with doses as low as 325 oocysts per animal. When sampled at weekly intervals postinoculation, guinea pigs had significant evidence of infection up to 2 weeks but had recovered completely by 4 weeks. Guinea pigs mounted a specific humoral immune response against cryptosporidia, as measured by an immunoperoxidase technique. Guinea pigs challenged by reinoculation with cryptosporidial oocysts were completely refractory to reinfection. These studies show that cryptosporidiosis in guinea pigs is a useful small animal model of this disease.