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The genetic and molecular basis of heterosis has long been studied but without a consensus about mechanism. The opposite effect, inbreeding depression, results from repeated self-pollination and leads to a reduction in vigor. A popular explanation for this reaction is the homozygosis of recessive, slightly deleterious alleles upon inbreeding. However, extensive studies in alfalfa indicated that inbreeding between diploids and autotetraploids was similar despite the fact that homozygosis of alleles would be dramatically different. The availability of tetraploid lines of maize generated directly from various inbred lines provided the opportunity to examine this issue in detail in perfectly matched diploid and tetraploid hybrids and their parallel inbreeding regimes. Identical hybrids at the diploid and tetraploid levels were inbred in triplicate for seven generations. At the conclusion of this regime, F1 hybrids and selected representative generations (S1, S3, S5, S7) were characterized phenotypically in randomized blocks during the same field conditions. Quantitative measures of the multiple generations of inbreeding provided little evidence for a distinction in the decline of vigor between the diploids and the tetraploids. The results suggest that the homozygosis of completely recessive, slightly deleterious alleles is an inadequate hypothesis to explain inbreeding depression in general.