The effect of chlorpromazine on the net intestinal accumulation of fluid induced by Escherichia coli heat-stable (ST) enterotoxin in an infant mouse model was examined. Chlorpromazine, when administered with ST enterotoxin, caused a highly significant decrease in net intestinal fluid accumulation. The inhibition of ST activity was dose dependent with various concentrations of chlorpromazine (P less than 0.001). A significant inhibition of toxic activity was also observed when chlorpromazine was administered before (P less than 0.02) or after (P less than 0.05) ST enterotoxin challenge. No significant differences in fluid accumulation were observed between control mice treated with buffer alone and those treated with only chlorpromazine. These data indicate that chlorpromazine markedly decreases the net intestinal fluid accumulation induced by E. coli ST enterotoxin. Further studies on the potential use of chlorpromazine in both the prophylaxis and the treatment of diarrheal diseases appear warranted.