Genetic heterozygosity is thought to enhance resistance of hosts to infectious diseases, but few tests of this idea exist. In particular, heterozygosity at the MHC, the highly polymorphic loci that control immunological recognition of pathogens, is suspected to confer a selective advantage by enhancing resistance to infectious diseases (the "heterozygote advantage" hypothesis). To test this hypothesis, we released mice into large population enclosures and challenged them with multiple strains of Salmonella and one of Listeria. We found that during Salmonella infections with three avirulent strains, MHC heterozygotes had greater survival and weight than homozygotes (unlike sham controls), and they were more likely to clear chronic Salmonella infection than homozygotes. In laboratory experiments, we found that MHC heterozygosity enhanced the clearance of multiple-strain Salmonella infections. Yet, contrary to what is widely assumed, the benefits of heterozygosity were due to resistance being dominant rather than overdominant, i.e., heterozygotes were more resistant than the average of parental homozygotes, but they were not more resistant than both. The fact that MHC heterozygotes were more resistant to infection and had higher fitness than homozygotes provides a functional explanation for MHC-disassortative mating preferences.