The purpose of our study was to learn whether changes in the external milieu could affect the lethality of ouabain. We found that guinea pigs experiencing restraint stress for the first time showed a greater susceptibility to the lethal effects of ouabain (175 microgram/kg IP) than non-stressed controls. Adaptation to the restraint procedure abolished this sensitization. This effect related to repeated experience with restraint and not to repeated human handling because repeatedly handled guinea pigs still showed sensitization to the lethal effect of ouabain (200 microgram/kg IP) when restrained for the first time. These data indicate that environmental factors will have to be considered in addition to changes in the internal milieu when trying to explain individual differences in sensitivity to toxicity while taking constant doses of digitalis.