The past two decades have seen an upsurge in detecting the genetic determinants of hypertension. Thereafter, alpha-adducin gene ranks high and one polymorphism, G460W (rs4961), has attracted special attention. We first performed a case-control study to investigate the association of this polymorphism with essential hypertension among Shanghai residents, and then meta-analyzed all available evidence. A total of 950 subjects were recruited for genetic association study. Genotyping for G460W was conducted using PCR and restriction fragment length polymorphism techniques. Meta-analysis search was limited to articles published in English and studies on humans. Data and study quality were assessed in duplicate. Publication bias was evaluated using the fail-safe number. Our case-control study provided no evidence for the association of G460W with essential hypertension, even under assumptions of three genetic modes of inheritance (P>0.05). The subsequent meta-analysis including 15 studies with 4417 cases and 5716 controls also failed to demonstrate overall this association, even upon stratification by race (Caucasians and Asians). For example, the summary odds ratio (OR) under a random effects model indicated that carriers of 460W allele were 1.09 times more likely to develop hypertension (95% confidence interval (CI), 0.96-1.24; P=0.19) among Asians, whereas a protective effect of this allele was observed in Caucasians (OR, 0.93; 95% CI, 0.73-1.18; P=0.54). The fail-safe number at the level of 0.05 was in favour of our findings. Our case-control study and the following meta-analysis failed to provide evidence for the genetic association of alpha-adducin gene G460W polymorphism with hypertension.