Perilipin coats intracellular lipid droplets and modulates adipocyte lipolysis. We have evaluated the association between several polymorphisms at the perilipin (PLIN) locus (PLIN1 : 6209T > C, PLIN4 : 11482G > A, PLIN5 : 13041A > G, and PLIN6 : 14995A > T) with obesity‐related phenotypes in 1589 White subjects randomly selected from a general Spanish population. In women (n = 801), the less common alleles of PLIN1 and PLIN4, in strong linkage disequilibrium (D′ : 0.96), were significantly associated with lower body mass index. Carriers of the allele 2 (6209C) at the PLIN1 locus weighed significantly less (−2.2 kg; p = 0.007) than women homozygotes for the wild‐type genotype. The same was true for 11482A carriers at PLIN4 (p = 0.01). Moreover, the PLIN4 variant was associated with significantly lower waist‐to‐hip ratio, plasma glucose, and triacylglycerol concentrations. No significant associations with these obesity‐related phenotypes were found in men. In agreement with these results, statistically significant gene–gender interactions were obtained when the risk of obesity was estimated (281 subjects were obese and 1308 non‐obese). Only in women, PLIN1 and PLIN4 variant alleles (6209C and 11482A) were associated with a lower obesity risk [Odds ratio (OR) = 0.58, 95% confidence interval (CI): 0.38–0.93 and OR = 0.56, 95% CI: 0.36–0.89, respectively]. In summary, our data suggest that common alleles at the PLIN locus modulate body weight and metabolic variables in humans.