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<p>Abstract</p> <p>Background</p> <p>Sulphadoxine and pyrimethamine are anti-folate drugs that show synergistic anti-malarial effect. Point mutations in <it>dihydrofolate reductase </it>(<it>dhfr</it>) and <it>dihydropteorate synthatase </it>(<it>dhps</it>) cause anti-folate drug resistance phenotype in human malaria parasites. This study presents pattern of point mutations in <it>dhfr/dhps </it>genes among Indian sub-continent.</p> <p>Methods</p> <p>Microscopically diagnosed one hundred <it>Plasmodium vivax </it>field isolates were collected from five widely separated geographical regions of India. <it>Dhfr </it>and <it>dhps </it>genes were PCR amplified and sequenced. Previously published mutations data were collected and analyzed using Chi square test to identify geographical cluster of mutant/wild type genotypes.</p> <p>Results</p> <p>Sequence analysis revealed single (S58R), double (S58R/S117N) and quadruple (F57L/S58R/T61M/S117T/) point mutations at <it>dhfr </it>and single (A383G) to double (A383G/A553G) mutations at <it>dhps </it>in <it>P. vivax </it>field isolates. In addition, three new mutations were also observed at <it>dhfr</it>. Both, <it>dhfr </it>and <it>dhps </it>genes revealed tandem repeat variations in field isolates. <it>Dhps </it>revealed very low mutation frequency (14.0%) compared to <it>dhfr </it>(50.70%). Comparative analysis revealed a progressive increase in frequency of quadruple mutant <it>dhfr </it>genotype (p < 0.001) within five years in north-eastern state (Kamrup, Assam). Frequency of <it>dhfr </it>genotypes revealed three distinct geographical clusters of wild (northern India), double mutant (southern India), and quadruple mutant (north-eastern and island regions of India) on the Indian sub-continent.</p> <p>Conclusion</p> <p>Study suggests that SP may be susceptible to <it>P. vivax </it>in India, except Andaman and north-eastern state. The distinction of geographical regions with sensitive and resistant parasite phenotypes would be highly useful for designing and administering national anti-malarial drug policy.</p>