Lymphotoxin-alpha (LTA) polymorphism rs909253 has been reported to be a risk factor for cancers, but some results are inconsistent. To establish a more conclusive association, we performed a meta-analysis of this variant with cancers. A systematic search was performed for informative case-control studies of rs909253 with cancers among literature databases, including PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang Chinese Periodical Database. After a comprehensive filtration procedure, 36 publications involved with 35,677 participants were selected for the current meta-analysis. Stratified factors, such as cancer type, populations, and source of control, were used for a better interpretation of this variant. Minimal heterogeneity was shown in the current meta-analysis (I (2) = 0.0%, P = 0.48). Our results show a significant association of rs909253 and cancer risk (odds ratio (OR) = 1.12, P (z) < 0.001). In the subgroup analysis, significant association of rs909253 was found in adenocarcinoma (OR = 1.16, P (z) < 0.001) and hematological malignancy (OR = 1.10, P (z) < 0.001). Our meta-analyses established a significant association of rs909253 with cancer risk among multiple populations including North Americans, Asians, and Europeans.