Mutations of the small heterodimer partner (SHP) gene have been associated with mild obesity in Japanese subjects. This study was designed to investigate whether there was a similar association in 772 Chinese adults. A total of 272 subjects were normal weight, 423 were overweight and 77 were obese. Four non-synonymous mutations (R34X, H53fsdel10, G171A, G189E) were identified in 10 out of the 500 overweight/obese subjects, but were not seen in the normal weight controls (prevalence 2.00% versus 0.00%, respectively). The relatives of proband carriers, including 25 carriers and 33 non-carriers from three generations, were also screened for 10 multigenerational non-consanguineous pedigrees. A gender-dependent penetrance effect was observed in the pedigrees. Furthermore, the frequency of SHP gene mutations was significantly higher in those with type 2 diabetes compared with the non-diabetics (61.5% versus 28.1%, respectively). These data provide evidence of a gender-dependent effect on penetrance for SHP deficiency and suggest that SHP mutations increase susceptibility to type 2 diabetes.