Clinical resistance to many therapies for malaria is a rapidly evolving problem in most endemic areas, particularly, Southeast Asia. Recent studies have suggested linkages between the mdr-like genes of Plasmodium falciparum and resistance to quinoline containing compounds. Other studies have found an association between allelic polymorphisms in the DHFR gene and antifol resistance in these parasites. The purpose of this study was to further examine these associations in recent isolates from Cambodia. DNA sequences and gene copy number of the pfmdr1 and the DHFR-TS gene in 10 Cambodian isolates were analyzed and correlated with the drug sensitivity pattern. No new intragenic alleles were detected in the pfmdr1 gene by a full-length DNA sequence analysis of the L-14/Cambodia clone. The allelic variations seen in pfmdr1 in these isolates did not correlate with chloroquine resistance as previously reported. The full-length sequence of the DHFR domain of the DHFR-TS gene revealed three or four point mutations in each Cambodian isolate. The latter findings may be correlated with high-level resistance to the antifolate drugs as has been previously described. None of the Cambodian isolates presented gene amplification in either pfmdr1 or DHFR-TS genes.