The hypothermic responses of mice that occur after acute injection of nicotine show genetic influences. The body temperatures of mice of all five strains tested decreased after injection of either 0.75 or 1.5 mg/kg nicotine, but mice of the C3H strain were less affected than were those of the DBA, BALB, or C57BL strains. Mice of the A strain were the most sensitive to nicotine's effects. Genetic effects on nicotine-induced hypothermia were further examined using a five-by-five diallel cross. Additive genetic variance occurred at both nicotine doses. Substantial dominance variance, including directional dominance toward a large hypothermic response induced by injection of a low dose of nicotine (0.75 mg/kg), suggested that an intense response to a low drug dose is adaptive. The directional dominance was absent after treatment with a high dose (1.5 mg/kg) of the drug. Epistatic interactions occurring in crosses involving C57BL mice were pronounced.