Purpose The proinflammatory cytokine tumor necrosis factor-α has an important role in the pathogenesis of prostate cancer. Single nucleotide polymorphisms in the promoter region of the TNF-A gene alter tumor necrosis factor-α transcription. Thus, we studied the association of 4 SNPs in the promoter region of TNF-A gene, including −1031T>C, −863C>A, −857 C>T and −308 G>A, in a North Indian cohort of patients with prostate cancer. Materials and Methods The study involved 453 subjects. All 197 case and 256 control samples were genotyped for the 4 promoter polymorphisms in the TNF-A gene using allele specific polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism. Results Results showed an increased risk of prostate cancer for the TNF-A −1031 CC genotype (OR 2.01, p = 0.03). No significant association was observed for the TNF-A −863 C>A, TNF-A −857 C>T or −308 G>A polymorphisms. Haplotype analysis revealed that TNF-A −1031C -863C -857T -308G was significantly associated with prostate cancer risk (OR 2.22, p = 0.013). Moreover, the TNF-A −1031 C and −857 T alleles were associated with higher tumor grade and an increased risk of tumor progression and metastasis. Conclusions These results show that TNF-A polymorphisms have an important role in prostate cancer pathogenesis. Results are in line with findings in other studies from the West and to our knowledge for the first time from India indicating the involvement of immune system genes in prostate cancer pathogenesis.