We assessed interactions between polymorphisms in the beta-adrenergic receptor genes and longitudinal changes in obesity from childhood to adulthood using longitudinal data collected over a 24-year period from 1973 to 1996. Sex- and age-stratified analyses using random coefficients models were used to examine gene-gene interaction effects on obesity measures in 1179 African-American and white men and women (71% white, 57% women). Suggestive evidence for an interaction (p = 0.022) between the beta1- and beta2-adrenergic receptors was observed in men for longitudinal change in BMI. Men with Gly/Gly genotypes for both the beta1 and beta2 receptors showed significant increases (approximately 0.6%/yr) in BMI from childhood to adulthood. Women showed suggestive evidence for an interaction (p = 0.035) between the beta1- and beta3-adrenergic receptors for change over time in BMI. Women with Gly/Gly genotypes at the beta1-receptor and carrying at least one beta3-Arg allele showed notable increases in BMI. The regulation of lipolysis and development of obesity differ markedly between men and women and may be influenced by genetic polymorphisms, which contribute to the efficiency of the beta-adrenergic receptors, and hormonal effects on adrenergic receptor activity.