Background: Genetic variation in the perilipin (PLIN) gene may play a role in the etiology and treatment of obesity. Objective: To examine different polymorphisms in the PLIN gene in relation to body-weight regulation. Methods: 118 subjects followed a 6 wk VLCD, followed by 1 year weight maintenance. Body-weight (BW), body-composition, leptin concentration, and polymorphisms of the PLIN gene: PLIN1:rs2289487, PLIN4:rs894160, PLIN6:rs1052700, PLIN5:rs2304795 and PLIN7:rs 2304796 were determined. Results: BW loss during VLCD was 7.0 ± 3.1 kg (p < 0.05), and BW regain was 3.7 ± 1.4 kg (p < 0.05), including changes in body mass index (BMI), waist-circumference, body-composition and leptin concentrations (p < 0.05). Linkage disequilibria were observed between PLIN1 and PLIN4: D' > 0.9, r2 = 0.72; PLIN5 and PLIN7: D' > 0.9, r2 = 0.85. In men, body weight, BMI, waist circumference, body fat, leptin concentrations were significantly lower for the haplotype of PLIN1 (C-alleles) and PLIN4 (A-alleles). In women weight loss and loss of fat mass were larger for the haplotype of PLIN1 (C-alleles) and PLIN4 (A-alleles). For PLIN6 genotypes body weight and body fat were lower for homozygotes of the minor allele (T/T) in the men; in the women leptin concentrations were lower. The haplotype of PLIN5 and PLIN7 consisting of A/G and G/G of PLIN5 and A/A of PLIN7 showed a reduction in FM: 5.9 ± 0.6 kg vs 3.1 ± 0.4 kg, % body fat: 5.5 ± 0.6% vs 2.2 ± 0.2%, and leptin: 20.5 ± 10.8 ng/ml vs 12.9 ± 6.7 ng/ml over time in the women (p < 0.05). Conclusion: Since the haplotype of the minor alleles PLIN1-4, PLIN5-7 and PLIN6, was related to body-weight regulation at a lower level of body-weight in the men as well in the women we conclude that the PLIN1-4, 6, and 5-7 locus appears as a genetic influencer of obesity risk in humans.