Summary Objective To monitor the efficacy of anti-malarial treatments in Thailand. Method A 28-day in vivo study in nine provinces along international borders in 2003. The first group comprised 164 patients from four provinces: Mae Hong Son, Chiang Mai, Ratchaburi and Ubon Ratchathani. These patients received 15 mg/kg mefloquine as a single dose. The second group, 58 patients from Kanchanaburi, were treated with 15 mg/kg mefloquine plus artesunate (12 mg/kg). The third group, 196 patients from provinces with high-level mefloquine resistance (Tak, Ranong, Chanthaburi and Trat), received 25 mg/kg of mefloquine plus 12 mg/kg artesunate. In all arms, follow-up blood smears were scheduled for days 1, 2, 3, 7, 14, 21 and 28. All patients tolerated the regimens well. Results The percentage of adequate clinical and parasitological response to mefloquine monotherapy was 62.0% in Mae Hong Son, 75.0% in Chiang Mai, 94.0% in Ratchaburi and 89.7% in Ubon Ratchathani. In Kanchanaburi, the percentage of adequate clinical and parasitological response to the artesunate–mefloquine combination was 94.2%. In the third group, this response exceeded 90%, except in Trat, where it was only 78.6% (44 patients). Conclusion Mefloquine monotherapy must urgently be replaced in Mae Hong Son and Chiang Mai. The markedly reduced efficacy of the artesunate–mefloquine combination used in Trat raises questions about the future of this therapy on the southeastern border of Thailand with Cambodia. It is very worrying because no practical and affordable alternative is yet available.