BACKGROUND: Human oxoguanine glycosylase 1 (hOGG1) in base excision repair (BER) pathway plays a vital role in DNA repair. Numerous epidemiological studies have evaluated the association between hOGG1 Ser326Cys polymorphism and the risk of cancer. However, the results of these studies on the association remain conflicting. To derive a more precise estimation of the association, we conducted a meta-analysis. METHODOLOGY/PRINCIPAL FINDINGS: A comprehensive search was conducted to identify the eligible studies of hOGG1 Ser326Cys polymorphism and cancer risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. We found that the hOGG1 Ser326Cys polymorphism was significantly associated with overall cancer risk (Cys/Cys vs. Ser/Ser: OR = 1.19, 95%CI = 1.09-1.30, P<0.001; Cys/Cys vs. Cys/Ser+Ser/Ser: OR = 1.16, 95%CI = 1.08-1.26, P<0.001). Moreover, in subgroup analyses by cancer types, the stronger significant association between hOGG1 Ser326Cys polymorphism and lung cancer risk was found (Cys/Cys vs. Ser/Ser: OR = 1.29, 95%CI = 1.16-1.44, P<0.001; Cys/Cys vs. Cys/Ser+Ser/Ser: OR = 1.22, 95%CI = 1.12-1.33, P<0.001). The significant effects of hOGG1 Ser326Cys polymorphism on colorectal, breast, bladder, prostate, esophageal, and gastric cancer were not detected. In addition, in subgroup analyses by ethnicities, we found that the hOGG1 Ser326Cys polymorphism was associated with overall cancer risk in Asians (Cys/Cys vs. Ser/Ser: OR = 1.21, 95%CI = 1.10-1.33, P<0.001). CONCLUSIONS: This meta-analysis showed that hOGG1 326Cys allele might be a low-penetrant risk factor for lung cancer.