IgG has a crucial role in humoral immune response. Serum IgG level is mainly determined under genetic control. To explore the genetic influence on serum IgG levels, a two-stage genome-wide association study (GWAS) was performed in a healthy Chinese population of 3495 men, including 1999 unrelated subjects in the first stage and 1496 independent individuals in the second stage. Three single-nucleotide polymorphisms (SNPs) located in TNFRSF13B on 17p11.2 or nearby were significantly associated with IgG level: rs4792800 in the intron (combined P-value=1.45 × 10(-12)), rs12603708 in the intron (combined P-value=1.82 × 10(-8)) and rs3751987 at ~65 kb downstream of the 5'-UTR region of TNFRSF13B (combined P-value=3.67 × 10(-9)). Additionally, smoking was identified to be associated with IgG level in both stages (P<0.001), but there was no significant interaction between smoking and the identified SNPs (P>0.05). The strong association between variants at TNFRSF13B and IgG level may be helpful to further explore the biological mechanism by which the serum IgG is affected by transmembrane activator, calcium modulator and cyclophilin ligand interactor encoded by TNFRSF13B.