Although principally considered a vector-borne disease, the vertical transmission of Trypanosoma cruzi from mother to child is now recognized as a significant and increasing threat to human health. Despite its importance, significant gaps exist in our understanding of the relationships between genotype, virulence, and the extent of vertical transmission of this pathogen. To better understand these relationships, we describe the comparison of a South American–derived Type I isolate (BS) of T. cruzi to a Type IIa isolate (SCI) of from North America for virulence and frequency of vertical transmission in BALB/c and outbred mice. Assays performed in BALB/c mice conclusively confirm the comparatively greater virulence of the BS isolate. Breeding experiments demonstrated a reciprocal relationship between virulence and the frequency of vertical transmission, with the pups born to Type IIa SCI–infected female mice testing positive at twice the frequency (66%) as those infected with the Type I BS (33%). Experiments carried out in BALB/c mice confirmed that an active infection with the SCI isolate generated immunity against a BS challenge. These results confirm that significant differences in the extent of vertical transfer can exist between T. cruzi isolates and contradicts the hypothesis that such transmission is a function of elevated maternal blood parasitemias. This study also provides support for some of the current hypotheses on attenuation during a pathogen's evolution from vector-borne to vertical transmission. We suggest that T. cruzi may provide a useful model for the study of the adaptive dynamics of a zoonotic human pathogen.