We conducted a decision analysis to compare the cost-effectiveness of antimicrobial agents used for treatment with their use for prophylaxis of travelers' diarrhea. Estimates of the likelihood and the cost of various outcomes were obtained from a panel of experts using the Delphi group opinion technique. Treatment with sulfamethoxazole-trimethoprim for three days was compared with daily prophylaxis with sulfamethoxazole-trimethoprim or doxycycline. The cost-effectiveness of prophylaxis with either agent (75% to 83%) was greater than that of treatment (38%). Treatment would become more cost-effective than prophylaxis when the cumulative risk of acquiring travelers' diarrhea was less than 0.05 episodes per person per week or if the effectiveness of prophylaxis fell below 35% for doxycycline and 46% for sulfamethoxazole-trimethoprim. The most important contributor to the mean cost of travelers' diarrhea in this analysis was the cost associated with a day of incapacitation due to illness. On the basis of the results of this decision analysis, we conclude that prophylaxis of travelers' diarrhea is an option that should be considered for individual situations and recommend further studies of its cost-effectiveness.