Abstract--Hyperuricemia is associated with cardiovascular risk. The present study examines the association between serum uric acid (UA) elevation and the 2-, 2-, and 3-adrenoceptor polymorphisms. In 219 nonobese, normotensive, normouricemic (serum UA <6.5 mg/dL at entry) men, serum UA, plasma norepinephrine (NE), the homeostasis model assessment of insulin resistance (HOMA-IR), body mass index, total body fat mass, the 2A(Lys418Asn)-, 2(Arg16Gly, Gln27Glu)-, and 3(Trp64Arg)-adrenoceptor polymorphisms were measured annually over 5 years. Hyperuricemia was defined as a serum UA level of mean+1 SD of 5.0 mg/dL in the participants. At entry, there were 36 subjects who had hyperuricemia and 183 who had normal UA levels. A significant UA elevation for 5 years was defined as an increase in 10% in UA levels. There were 82 subjects who had significant UA elevations. The subjects who had hyperuricemia at entry in addition to the subjects who had significant UA elevations over the 5-year period carried a significantly higher frequency of the Asn418 allele of Lys418Asn. Additionally, subjects carrying the Asn418 allele had higher UA and plasma NE and greater elevations in UA over the study period, but HOMA-IR was similar. Insulin resistance at entry and during the study was associated with Arg16Gly polymorphisms but not with Lys418Asn polymorphisms. In conclusion, the Asn418 allele of Lys418Asn is associated with either established hyperuricemia or the progressive elevation of UA over time. This polymorphism was not associated with insulin resistance in nonobese, normotensive individuals. Although hyperuricemia is of known relevance to insulin resistance, it appears to have different genetic determinants from insulin resistance in terms of adrenoceptor polymorphisms.