Abstract The extracellular matrix (ECM) of adipocytes is important for body weight regulation. Here, we investigated whether genetic variation in ECM-related genes is associated with weight regain among participants of the European DiOGenes study. Overweight and obese subjects (n = 469, 310 females, 159 males) were on an 8-week low-calorie diet with a 6-month follow-up. Body weight was measured before and after the diet, and after follow-up. Weight maintenance scores (WMS, regained weight as percentage of lost weight) were calculated based on the weight data. Genotype data were retrieved for 2903 SNPs corresponding to 124 ECM-related genes. Regression analyses provided us with six significant SNPs associated with the WMS in males: 3 SNPs in the POSTN gene and a SNP in the LAMB1, COL23A1, and FBLN5 genes. For females, 1 SNP was found in the FN1 gene. The risk of weight regain was increased by: the C/C genotype for POSTN in a co-dominant model (OR 8.25, 95 % CI 2.85–23.88) and the T/C–C/C genotype in a dominant model (OR 4.88, 95 % CI 2.35–10.16); the A/A genotype for LAMB1 both in a co-dominant model (OR 18.43, 95 % CI 2.35–144.63) and in a recessive model (OR 16.36, 95 % CI 2.14–124.9); the G/A genotype for COL23A1 in a co-dominant model (OR 3.94, 95 % CI 1.28–12.10), or the A-allele in a dominant model (OR 2.86, 95 % CI 1.10–7.49); the A/A genotype for FBLN5 in a co-dominant model (OR 13.00, 95 % CI 1.61–104.81); and the A/A genotype for FN1 in a recessive model (OR 2.81, 95 % CI 1.40–5.63). Concluding, variants of ECM genes are associated with weight regain after weight loss in a sex-specific manner.