New antibiotics are required to have the antibacterial activity against doxycycline-resistant Orientia tsutsugamushi. An in vitro sensitivity study showed that telithromycin was more effective than erythromycin for Rickettsia, Bartonella, and Coxiella burnetii. In this prospective, open-label, randomized trial, we enrolled patients with mild-to-moderate scrub typhus. We compared the efficacy and safety of a 5-day telithromycin therapy with those of a 5-day doxycycline therapy at Chosun University Hospital or one of its two community-based affiliated hospitals (Jangheung Hospital and Cheomdan Hospital), which are all located in southwestern Korea, between September and December 2005. A total of 92 patients were randomly assigned to either the telithromycin group (n = 47) or the doxycycline group (n = 45). After the treatment, fever control time was 20.45 +/- 12.9 h in the telithromycin group and 22.60 +/- 21.44 h in the doxycycline group (P > 0.05). After the treatment, the cure rate was 100% in the telithromycin group and 97.8% in the doxycycline group (P > 0.05). Furthermore, there were no significant differences in time elapsed until such symptoms as headache, myalgia, and rash disappeared. No serious adverse events or death were noted following the treatment in both groups. There were no significant differences in adverse events. In conclusion, the efficacy and safety of a 5-day once-a-day regimen of 800 mg telithromycin were equivalent to those of a 5-day twice-a-day regimen of 100 mg doxycycline in patients with mild-to-moderate scrub typhus. Telithromycin could be considered a promising new antibacterial agent for patients with scrub typhus.