To investigate associations and gene-environment interactions of APOA-IV gene polymorphisms with obesity-related phenotypes in a Brazilian population. A total of 391 individuals (171 men and 220 women) were genotyped for Xbal, Thr347Ser and Gln360His polymorphisms by PCR-RFLP methods. Adjusted body mass index (BMI) and waist circumference (WC) were compared among genotypes/haplotypes by unpaired t-test or analysis of variance. Gene-environment interactions were tested by analysis of variance using a general linear model. Analysis of the APOA-IV gene variants separately showed that X*2 and 347Ser alleles were associated with higher BMI (P=0.02 for both polymorphisms). Haplotype analysis confirmed this association. For these polymorphisms, the effect on BMI appeared to depend on smoking status (test for interaction, P=0.007 and 0.02, respectively), the Thr347Ser variant was associated with a BMI increase in smokers only (P=0.002). At the single-locus level no association was observed between 360His allele and BMI; however, haplotype analyses showed an association of this gene variant and higher BMI. A trend for association with WC (P=0.05) was observed in male carriers of the 360His allele. The effect of this polymorphism also depended on smoking status (test for interaction, P=0.018). Nonsmoker male carriers of the 360His allele had a larger waist circumference than homozygotes for the Gln allele (P=0.003). Our data suggest that the APOA-IV gene polymorphisms investigated are associated with obesity-related traits. The effects of X*2 and 347Ser variants on BMI and the 360His variant on waist circumference depended on smoking status.