Genomic conflicts often arise because not all genes are inherited in the same way. Opportunities for conflict between the biparentally inherited nuclear genome and the maternally inherited mitochondrial genome (mtDNA) seem especially favorable and conflicts between nuclear and mitochondrial genes over sex determination and sex ratio have been well documented. In general, because genes in the mitochondrial genome are strictly maternally inherited, mutations that are beneficial in females can spread in a population even if they are somewhat deleterious in males. This phenomenon has been dubbed the “mother’s curse”. The accumulation of male-biased mutations in the mitochondrial genome should lead to selection in males for compensatory nuclear modifier loci that alleviate the effect. The Y chromosome, being strictly paternally inherited, has been suggested as a good candidate for such modifiers. Recent work has countered classic predictions by finding that loci in the mitochondrion and the Y chromosome can affect the expression of nuclear autosomal loci. Moreover, several of the autosomal loci shown to be affected by mitochondrial variation overlap with autosomal loci affected by variation on the Y chromosome. The extent to which these loci are subject to mtDNA-Y chromosomal epistatic effects and determine male health and fitness, however, remains unknown. To experimentally examine the extent to which mitochondrial and Y-linked genetic variants interact to determine male fitness, we used Drosophila melanogaster strains from the five geographical locations (Ithaca, the Netherlands, Zimbabwe, Beijing, and Tasmania). Through crosses, we generated strains that differed only in the geographical origin of their mitochondrial genome and the Y chromosome. If Y-linked suppressors are important, co-evolved combinations of the mitochondrial genome and the Y chromosome from the same population should outperform novel combinations. We present evidence that the effect of mtDNA-Y interactions depend both the origin of the mtDNA and the Y chromosome, as well as on what aspect of male fitness measured. In light of these results, we outline a simple model for how mtDNA-sex chromosome interactions differ in an XY compared to a ZW sex chromosome system where the female is the heterogametic sex, and the W chromosome is always co-transmitted with the mitochondrion.