Several lines of evidence suggest the importance of the estrogen receptor (ER) in determining body mass index (BMI). Our purpose was to investigate whether genetic polymorphisms at the restriction enzyme PvuII site of the ER-alpha gene locus are associated with BMI variation. Data on BMI, age, and ER-alpha genotypes were obtained from 108 healthy midwestern U.S. postmenopausal Caucasian women. The study subjects were unrelated and aged 65 yr and over (mean age +/- SD, 73.4 +/- 5.1 yr), with an average BMI of 25.25 (SD, 4.04). The ER-alpha genotypes were obtained by PCR followed by restriction enzyme PvuII digestion. We found that in our study subjects the ER-alpha genotypes are significantly associated with BMI (by ANOVA, P = 0.04), explaining about 6.2% of the BMI variation in our study sample. The allelic effects of this locus on BMI are approximately additive. In our sample, individuals of the PP and Pp genotypes have, respectively, 11.4% and 4.8% higher BMI than individuals of the pp genotype. There is a significant ER-alpha genotype by age interaction, so that in our sample PP individuals tend to gain weight with age, whereas Pp and pp individuals tend to lose weight with age. Therefore, the ER-alpha polymorphisms are associated with BMI variation in healthy postmenopausal Caucasian women aged 65 yr and over. Our result is consistent with some recent findings suggesting the potential effects of the ER on BMI. The importance of the ER-alpha genotypes in other populations and other age groups needs to be demonstrated. Although the results of the ER-alpha genotype by age interaction are obtained here from cross-sectional data, direct confirmation may come from longitudinal studies in which individuals are measured multiple times over several years. The importance of the ER-alpha genotypes on BMI should be confirmed by further studies using methods robust to the potential problem of population substructuring that may confound the conclusions of population association studies.