The objective of this investigation were to compare infectivity of Cryptosporidium parvum oocysts in CD-1 mice, HCT-8 cells, MDCK cells, and Caco-2 cells, to determine whether the different models vary in their sensitivity to infection, generate different dose responses, or vary in their ability to measure oocyst inactivation. In general, cell culture was at least as sensitive as the CD-1 mouse model for measuring the infectivity of fresh oocysts. However, considerable variation existed in all models. In some instances the shape of the dose response curve derived from cell culture was indistinguishable from the curve for mice. For all genotype 2 isolates (n = 5), the Caco-2 cell line was least receptive to infection. The ID50 values for the 5 isolates ranged from 21 - 215 in CD-1 mice, 19 - 87 in HCT-8 cells, 2 - 85 in MDCK cells, and 43 - 327 in Caco-2 cells. A genotype 1 isolate (non-infectious in mice) had an ID50 of 631 oocysts in HCT-8 cells, although this could not be directly compared with the data for genotype 2 isolates since the genotype 1 oocysts were considerably older and stored under non-ideal conditions. This is the first rigorous comparison of cell culture with an animal model for C. parvum, using precisely enumerated oocyst doses, and the results with five isolates demonstrated that infectivity in cell culture may be a good indicator of the ability of oocysts to cause infection in animals. This study demonstrated that in-vitro cell culture is equivalent to a standard mouse model for measuring infectivity of C. parvum oocysts. Includes 19 references, table, figures.