To identify risk factors associated with heatstroke, a case-control study in St Louis and Kansas City, Mo, was conducted during July and August 1980. Questionnaire data were gathered for 156 persons with heatstroke (severe heat illness with documented hyperthermia) and 462 control subjects matched by age, sex, and neighborhood of residence. A stepwise linear logistic regression procedure was used to identify factors significantly associated with heatstroke. Alcoholism, living on the higher floors of multistory buildings, and using major tranquilizers (phenothiazines, butyrophenones, or thioxanthenes) were factors associated with increased risk. Factors associated with decreased risk were using home air conditioning, spending more time in air-conditioned places, and living in a residence well shaded by trees and shrubs. Being able to care for oneself, characteristically undertaking vigorous physical activity, but reducing such activity during the heat, and taking extra liquid were also associated with decreased risk. Our findings also suggest effective preventive measures. During a heat wave, the greatest attention should be directed toward high-risk groups, and relief efforts should include measures shown to be associated with reduced risk.