SummaryBackground  The metabolic syndrome (MS), a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for cardiovascular disease. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), originally described as a plasma cell allo‐antigen and named plasma cell membrane glycoprotein (PC‐1), is an inhibitor of insulin‐induced activation of the insulin receptor. The single nucleotide polymorphism (SNP) K121Q in the ENPP1 gene has been studied in relation to obesity, insulin resistance and other features of MS in several populations with conflicting results.We therefore investigate the role of the K121Q SNP in the ENPP1 gene in MS in Caucasians from the province of Segovia in Central Spain (Castille).Design and methods  We recruited 794 unrelated persons (46·5% males and 53·5% females), ages 35–74 years from a cross‐sectional population‐based epidemiological survey in the province of Segovia in Central Spain (Castille). Obesity‐related anthropometric measurements included BMI, waist circumference, blood pressure and lipid profile. MS was defined by International Diabetes Federation (IDF) guidelines. K121Q PC‐1 genotypes were determined by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP).Results  The 121Q allele was associated with an increased BMI and waist circumference among subjects fulfilling the criteria for MS. These differences remained statistically significant even after the adjustment for sex, age and degree of glucose tolerance (β = 1·347, P = 0·017 and β = 2·824, P = 0·046; for BMI and waist circumference, respectively). Moreover, among type 2 diabetic patients those carrying the 121Q allele had higher BMI and higher leptin levels than subjects carrying the K121K genotype.Conclusions  Our results suggest that the ENPP1121Q allele might contribute to the genetic susceptibility to abdominal obesity among subjects with MS.