Purpose: Previous investigations suggest that inhaled anesthetics may produce cutaneous analgesia. The objective of this study was to evaluate whether inhaled anesthetics have a direct analgesic effect on skin. Methods: We conducted subcutaneous injections of one of three inhaled anesthetics (halothane, isoflurane, and enflurane) or one of two local anesthetics (lidocaine and procaine) at various dosages in rats (n=6 rats, for each dose of each drug). Subcutaneous injections of vehicles (saline or olive oil) were used as controls (n=6 rats for each vehicle). We constructed concentration-response curves, wherein the concentrations of drugs tested in subcutaneous tissue fluid were estimated by calculation, and the cutaneous analgesic effects of drugs were evaluated by pinprick tests on skin. Results: Like local anesthetics, subcutaneous injection of inhaled anesthetics produced concentration-dependent, cutaneous analgesia which attained maximum (complete cutaneous analgesia) at high concentration. This effect was reversible and localized in the area of injection. On the basis of 50% effective concentration, the ranking of potencies was lidocaine > halothane > isoflurane > enflurane > procaine (P<0.05 for all differences). Subcutaneous injections of vehicles did not produce cutaneous analgesia. Conclusions: Like local anesthetics (lidocaine and procaine), subcutaneous injections of inhaled anesthetics (halothane, isoflurane, and enflurane) produced a concentration-dependent, cutaneous, analgesic effect at the site of injection. Inhaled anesthetics have a direct analgesic effect on skin.