In the mouse model for systemic infection, natural a/α strains of C. albicans are more virulent and more competitive than their spontaneous MTL-homozygous offspring, which arise primarily by loss of one chromosome 5 homologue followed by duplication of the retained homologue (uniparental disomy). Deletion of either the a or α copy of the MTL locus of natural a/α strains results in a small decrease in virulence, and a small decrease in competitiveness. Loss of the heterozygosity of non-MTL genes along chromosome 5, however, results in larger decreases in virulence and competitiveness. Natural MTL-homozygous strains are on average less virulent than natural MTL-heterozygous strains and arise by multiple mitotic cross-overs along chromosome 5 outside of the MTL region. These results are consistent with the hypothesis that a competitive advantage of natural a/α strains over MTL-homozygous offspring maintains the mating system of C. albicans.