Vascular endothelial growth factor (VEGF) is an endothelial cell-specific potent mitogen involved in a number of pathologic processes, including angiogenesis, tumor growth, and metastasis. Polymorphisms of VEGF gene have been associated with susceptibility to several cancers. VEGF gene susceptibility to bladder cancer (BC), however, still remains controversial. We analyzed association of the -2578C/A, -7C/T, -2549I/D, and -1001G/C polymorphism of the VEGF gene with bladder cancer (BC) risk and interaction of these polymorphisms with lifestyle and demographic factors. We genotyped -2578C/A, -7C/T, -2549I/D and -1001G/C by PCR-restriction fragment length polymorphism and amplification refractory mutation specific method to evaluate risk in 200 BC patients and 250 healthy controls from North Indian population. Significant association for BC risk in heterozygous CA genotype (1.69-fold) in VEGF-2578C/A and heterozygous genotype of VEGF-1001G/C (p = 0.032) was observed. Interestingly, VEGF-2549I/D genotype showed reduced risk for BC. The gene-gene combination analysis revealed DD-GG with reduced risk (p = 0.018) of VEGF-2549I/D and VEGF-1001G/C, and combination CA-GG of VEGF-2578C/A and VEGF-1001G/C demonstrated 1.75-fold risk for BC. Our findings suggested that polymorphism -2578C/A and -1001G/C in the promoter of VEGF gene may play a significant role in mediating the bladder cancer risk, whereas VEGF-2549I/D genotype appears to be protective for BC.