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Cytochrome P450 expression in liver is influenced by several factors, including sex and strain. Whereas little is known about their metabolic capabilities, Hairless rats are widely used for the studies of tropical agents. We compared Sprague-Dawley and Hairless rat metabolic behavior to validate the use of Hairless rats in pharmacokinetic and metabolic studies of topically applied drugs. Liver microsomes of male and female rats of both strains were used to investigate the in vitro metabolism of three retinoic acid (RA) isomers: all-trans-RA, 13-cis-RA, and 9-cis-RA. In all cases, a major isomerization of the tested isomer in the two others was observed. This process was independent of the presence of NADPH, but depended on the presence of microsomal proteins. In addition, we observed, to a lesser extent, the formation of 4-oxo metabolites (4-oxo-all-trans-RA, 4-oxo-13-cis-RA, and 4-oxo-9-cis-RA), with the rate of formation of each of these compounds varying with the nature of the isomer incubated. The 4-oxo metabolites formed were statistically greater in male than in female rats in the two strains studied. No significant difference in RA biotransformation was observed between Sprague-Dawley and Hairless rats. In addition, no major difference was observed between the two strains concerning the expression of the different cytochrome P450 isoforms studied. In conclusion, phase I metabolism of RAs characterized by C4-hydroxylation varied with sex, but not within the two strains studied in rats. These results strengthen the relevance of the use of Hairless rats in pharmacokinetic and metabolic studies of topical agents, including retinoids.