Age and body temperature alter inhalational anesthetic requirement; however, no human genotype is associated with inhalational anesthetic requirement. There is an anecdotal impression that anesthetic requirement is increased in redheads. Furthermore, red hair results from distinct mutations of the melanocortin-1 receptor. Therefore, the authors tested the hypothesis that the requirement for the volatile anesthetic desflurane is greater in natural redheaded than in dark-haired women. The authors studied healthy women with bright red (n = 10) or dark (n = 10) hair. Blood was sampled for subsequent analyses of melanocortin-1 receptor alleles. Anesthesia was induced with sevoflurane and maintained with desflurane randomly set at an end-tidal concentration between 5.5 and 7.5%. After an equilibration period, a noxious electrical stimulation (100 Hz, 70 mA) was transmitted through bilateral intradermal needles. If the volunteer moved in response to stimulation, desflurane was increased by 0.5%; otherwise, it was decreased by 0.5%. This was continued until volunteers "crossed over" from movement to nonmovement (or vice versa) four times. Individual logistic regression curves were used to determine desflurane requirement (P50). Desflurane requirements in the two groups were compared using Mann-Whitney nonparametric two-sample test; P < 0.05 was considered statistically significant. The desflurane requirement in redheads (6.2 vol% [95% CI, 5.9-6.5]) was significantly greater than in dark-haired women (5.2 vol% [4.9-5.5]; P = 0.0004). Nine of 10 redheads were either homozygous or compound heterozygotes for mutations on the melanocortin-1 receptor gene. Red hair seems to be a distinct phenotype linked to anesthetic requirement in humans that can also be traced to a specific genotype.