The effect of indomethacin on the net intestinal accumulation of fluid induced by Escherichia coli heat-stable (ST) enterotoxin in the infant mouse model was examined. Indomethacin, when administered with ST enterotoxin, caused a striking decrease in net intestinal fluid accumulation. This inhibition of ST activity was dose dependent with various concentrations of indomethacin (P less than 0.01). A significant inhibition of toxicity was also observed when indomethacin was given before (P less than 0.01) or after (P less than 0.02) ST enterotoxin challenge. No significant differences in fluid accumulation were observed between control mice treated with buffer alone and those challenged with only indomethacin. These data indicate that indomethacin markedly decreases the net intestinal fluid accumulation induced by E. coli ST enterotoxin. Further studies on the potential use of indomethacin in both the prophylaxis and the therapy of diarrheal diseases appear warranted.