A new isolate of Trypanosoma musculi has been derived from organisms recovered from Mus spretus captured in Lisbon, Portugal. The time-course and profiles of infection with this isolate in inbred mice have been compared with those obtained with the existing Partinico II isolate. Infections with the Portuguese isolate are less intense, and controlled more quickly than those with the Partinico isolate. As with the latter, there are marked mouse strain-dependent influences on infection with the Portuguese isolate, but these strain-dependent characteristics differ considerably with each isolate. For example, NIH mice were the most susceptible to the Partinico II isolate, but virtually refractory to the Portuguese isolate. Mice exposed to infection with one isolate show complete immunity to both homologous and heterologous challenge infections. These striking interactions between host and parasite genotype are discussed in terms of immunological influences on infection.