Inherited polymorphic sequence variations in drug transport genes like impact a portion of patients with hematologic malignancies that show intrinsic or acquire resistance to treatment. Keeping in view inter-individual sensitivities for such drugs, we through this case-control study tested whether C3435T and G2677T polymorphisms have any influence on the risk and treatment response in patients with chronic myeloid leukemia (CML) and B-acute lymphoblastic leukemia (B-ALL). Genotyping for polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism in 100 CML and 80 B-ALL patients along with 100 age and gender matched healthy controls. C3435T and G2677T polymorphism showed no association with CML. Genotype distribution revealed significant higher frequency of TT genotype for both SNPs in B-ALL cases and associated with increased B-ALL risk (OR 2.5,  = 0.04 for 3435TT; OR 2.4,  = 0.04 for 2677TT). There was no significant difference in genotype frequency of 3435C > T and 2677G > T among resistant and responsive groups for the two leukemia types. Kaplan-Meier survival plots revealed significantly lower event free survival in CML and B-ALL patients that were carriers of 3435TT genotype ( < 0.05). Multivariate analysis considered 3435TT genotype as independent risk factor for imatinib resistance in CML cases (HR 6.24,  = 0.002) and increased relapse risk in B-ALL patients (HR 4.51,  = 0.03). The current study provides preliminary evidence of a significant association between variant TT genotype and increased B-ALL risk. Also, results suggest that 3435TT genotype increases imatinib resistance in CML and influence therapeutic outcome in B-ALL.