The interaction between human host and the Plasmodium parasite is complex. The factors affecting the causality of infection and its severity are yet not completely understood. Single Nucleotide Polymorphisms (SNP) associated with CR1 may be associated with patho-physiology of malaria and its susceptibility to the disease. Methods: The objective of the present study was to calculate the incidence of various antigens of Knops blood group system and CR1 Exon22 polymorphisms in rural population from Chiplun Taluka of Ratnagiri district. The study included 112 malaria positive cases and 909 healthy controls, which were screened for CR1 Exon22 polymorphism. Knops (Kna/b), McCoy (McCa/b), Swain-Langley (Sl1/2) polymorphisms were screened in 93 cases and 321 healthy controls. The frequencies were determined using a PCR-RFLP technique. Results: Only wild types of the allele form were observed in Knops blood group system in malaria cases and healthy control. CR1 exon22 polymorphism was seen in the study population with all the 3 allele type distributed in the cases and control samples. No significant allelic or genotypic differences were found between the controls and the disease groups. Conclusion: The results of the present study demonstrate that common CR1 Exon22 and Knops blood group system are not associated with malaria in the endemic area.