We conducted a prospective randomized double blind study on the effects of doxycycline as a prophylactic antibiotic against scrub typhus. A total of 1,125 military subjects was followed for periods as long as 5 months of exposure in a hyperendemic focus in the Pescadores Islands of Taiwan. Oral 200 mg doses of doxycycline (Vibramycin®) or placebo were given once each week throughout the trial. The incidence rate of scrub typhus in the placebo group was 2.5 times greater than that of the group taking doxycycline (P = 0.11). When subjects who failed to comply with scheduled administration of doxycycline were removed from the analysis, the incidence rate of scrub typhus in the control group was five times greater than that in the drug group (P = 0.04). The rates of infection with Rickettsia tsutsugamushi and of sick call reports were the same in experimental and control groups. The drug was well tolerated in pretrial tests and complaints were negligible during the conduct of the trial. Doxycycline appears to be an excellent antibiotic for the prevention of scrub typhus among personnel exposed to high risk of infection with R. tsutsugamushi.