In south-eastern Iran, the sulfadoxine-pyrimethamine (SP) combination has been used to treat malaria caused by chloroquine-resistant Plasmodium falciparum. To explore the molecular basis of antimalarial resistance in this region, the dhfr, dhps and pfcrt genes of 50 clinical isolates of P. falciparum, collected from cases of uncomplicated malaria in 2000-2001, were checked for the point mutations that appear associated with SP or chloroquine (CQ) resistance. The results of the study, which was based on a PCR followed by DNA sequencing, indicated that all 50 isolates presented the DHFR S108N mutation associated with pyrimethamine resistance. Seven isolates (14%) had a triple DHFR mutation (S108N, N51I, C59R) and 32 (64%) had a double mutation in this domain. Thirty-nine isolates (78%) had the wild-type DHFR 51 codon but only 15 (30%) had the wild-type DHFR 59 codon. Eleven isolates (22%) only had the DHFR S108N mutation. All isolates had the wild-type DHPS 436 and 540 codons and all but two of the isolates had the wild-type DHPS 437 codon. All isolates but one had the PFCRT K76T mutation associated with CQ treatment failure. The results of this preliminary investigation indicate that SP may remain the treatment of choice for cases of uncomplicated malaria in south-eastern Iran.