Primary immune thrombocytopenia (ITP) is manifested by platelet autoantibodies that are not only responsible for platelet destruction by phagocytosis but also inhibit their production. Bleeding is the most common clinical manifestation of thrombocytopenia. ITP is a multifactorial disease in which both environmental and genetic factors have been implicated. It has been reported that several gene polymorphisms influence host susceptibility to ITP. This study was aimed to investigate the association of polymorphisms in tumor necrosis factor-alpha (TNF-α) 308 G>A and TNF-β +252 A>G genes with primary ITP in Indian patients. Genotyping for the TNF-α −308 G>A and TNF-β +252 A>G was performed in 80 ITP patients and 100 controls by polymerase chain reaction and restriction fragment length polymorphism. We found no significant difference in distribution of TNF-α heterozygous variant genotype (GA) among patients and controls. Homozygous variant genotype (AA) was absent both in patients and controls. No statistical difference was observed in the distribution of heterozygous variant (AG) and homozygous variant (GG) genotypes of TNF-β, between patients and controls. Heterozygous (AG) genotype of TNF-β −308G>A was associated with persistent ITP. The study showed that heterozygous variant (AG) genotype of TNF-β was associated with persistent ITP, when compared with controls. We could not find any association of TNF-α with susceptibility in developing ITP. Furthermore, no association was observed with respect to different categories of ITP. In addition, additive model showed two-fold increased susceptibility to ITP. We conclude that single nucleotide polymorphism in TNF-β +252 A>G gene may have impact on susceptibility to ITP.