Knowledge of the frequency, distribution, and fate of lethal genes in chromosomal inversions helps to illuminate the evolution of recently founded populations. We analyze the relationship between lethal genes and inversions in two colonizing populations of D. subobscura in Chile. In the ancestral Palearctic populations of this species, lethal genes seem distributed at random on chromosomes. But in colonizing American populations, some lethal genes are associated with specific chromosomal arrangements. Some of these associated lethals were detected only during the first stages of the colonization (O 3?4?2 ), and never thereafter, whereas others have persisted (O 3?4?7 and O 5 ). However, most lethal genes in American populations have been observed only once: they have arisen by novel mutation and soon disappear. Finally, recombination between different inversions has been observed in America. However, the persistence of lethal genes associated with the heterotic inversions O 3?4?7 and O 5 could indicate that recombination inside these inversions is rare.