BACKGROUND: CD38 was found to rule proliferation signals in chronic lymphocytic leukemia (CLL) cells, suggesting that the molecule is not merely a prognostic marker but also a key element in the pathogenetic network underlying the disease. OBJECTIVE: We aimed at determining whether polymorphisms of CD38 gene influence the risk of B-CLL. Patients and METHODS: we analysed two potentially functional CD38 SNPs; intronic rs6449182 (184C>G) and missense rs1800561 (418C>T, Arg140Trp) using PCR- RFLP based assays in a study including 35 B-CLL patients and 35 age- and gender- matched controls. RESULTS: Our results demonstrated that frequencies of both mutant alleles (rs6449182G and rs1800561 T) were significantly higher and confer an increased risk for B-CLL [p value 0.002, OR=7.11, CI=1.82-27.79 and p value 0.011, OR=2.25, CI=1.70-2.96 respectively]. It was also found that that rs6449182 G and rs1800561 T carriers had more advanced clinical stage (p value <0.001). A significant association was demonstrated between higher proportions of CD38-positive cells and carriers of rs6449182 G and rs1800561 T alleles (p value <0.001). CONCLUSION: our data suggest that CD38 SNPs may contribute to increased risk of B-CLL.