We recently identified a mutation in the human β3-adrenergic receptor (β3AR) gene (codon 64 TGG(Trp)→CGG(Arg); TRP64ARG) that associates with features of the insulin resistance syndrome and an earlier onset of noninsulin-dependent diabetes mellitus (NIDDM). We scanned the β3AR gene for mutations by single stranded conformational polymorphism analysis in 20 Nauruans with obesity and NIDDM. No mutations were identified. Sixty-five Nauruan subjects were genotyped for the TRP64ARG β3AR. All subjects were homozygous for the normal allele. We genotyped Samoans and Asians for the TRP64ARG β3AR. Seven of 52 Samoans were heterozygous for the mutant arginine allele (allele frequency, 0.07). Of these, 5 were diabetic and 2 were nondiabetic (by Fisher's exact test, P = 0.4). There were trends toward increased body mass indices, waist to hip ratios, and 2-h insulin levels during oral glucose tolerance tests in Samoans with the mutation; however, the limited number of subjects available for study precluded rigorous statistical analysis. The TRP64ARG β3AR was also detected in Chinese, Chinese Americans, and subjects from the Indian subcontinent. In conclusion, the TRP64ARG β3AR mutation or any other mutation in the β3AR gene is not a major contributor to genetic susceptibility to NIDDM and obesity likely in Nauruans.