A prospective, open, randomized, comparative treatment trial was conducted to compare the therapeutic efficacy of the conventional four‐drug combination (chloramphenicol, trimethoprim‐sulfamethoxazole, and doxycycline) with that of doxycycline alone in oral maintenance treatment of melioidosis. Adult Thai patients with culture‐confirmed melioidosis were randomized to receive treatment with either regimen for a minimum of 12 weeks, usually following intravenous treatment of severe disease. The main outcome measure was culture‐confirmed relapse. One hundred sixteen patients were enrolled; 109 had culture‐confirmed melioidosis, and 87 were considered evaluable (43 had received doxycycline). Culture‐confirmed relapse occurred in one patient randomized to the conventional regimen and in 11 (25.6%) randomized to the doxycycline regimen (P = .009), and treatment failed for 8 (18.2%) versus 20 (46.5%), respectively (P = .009). Adverse effects occurred in 26% of patients overall. Doxycycline alone cannot be recommended for a first‐line regimen of oral maintenance treatment of melioidosis.