Objective Findings from the previous studies have suggested a relationship between ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP-1) or plasma cell membrane glycoprotein 1 (PC-1) gene single nucleotide polymorphism (K121Q, rs1044498) and genetic susceptibility to obesity. However, such relationship is not reproduced by some currently available studies. In this context, the present study is aimed to quantitatively analyze the association of K121Q variant with obesity in all published case-control studies in European adult populations. Methods Published literature from PubMed, EMBASE, and ISI web of science databases were retrieved. The studies evaluating the association of ENPP1/PC1 gene K121Q polymorphism with obesity were included, in which sufficient data were presented to calculate the odds ratio (OR) with 95% confidence intervals (Cls). Results Ten case-control studies meeting the inclusion criteria identified a total of 24,324 subjects including 11,372 obese and 12,952 control subjects. The meta-analysis results showed a statistically significant association of K121Q with obesity [OR (95%Cl): 1.25 (1.04-1.52) P=0.021] under a recessive model of inheritance (QQ vs. KK+KQ) without heterogeneity or publication bias. Conclusions The results from the present study have indicated that ENPP1/PC1 Q121 variant may increase the risk of obesity and that more well-designed studies based on a larger population will be required to further evaluate the role of ENPP1/PC1 gene K121Q, polymorphism in obesity and other related metabolic syndromes.