Objective：To investigate the relationship of genetic variations in MAPK/ERK pathway with knee osteoarthritis risk. Methods：A case-control study was conducted including 278 patients with knee osteoarthritis and 289 age and sex matched healthy controls. A total of 5 potentially functional variations in MAPK/ERK pathyway（MEK1，MEK2，ERK1 and ERK2）selected by RegulomeDB were genotyped by using SequenomMassARRAY. Univariate and multivariate logistic regression models were used to evaluate the association and its strength. Results：In univariate analysis，rs350911 of MEK2 was significantly associated with knee osteoarthritis in recessive model（TT vs. TC+CC）（OR=2.62，95% CI：1.70~4.02，P < 0.01）. After adjustment for age，gender and BMI，the associations remain significant（OR=2.72，95% CI：1.75~4.22，P < 0.01）. The stratification analyses revealed that the effect of rs350911 on knee osteoarthritis was significant in male，lower BMI（<25 kg/m2），and lower Kellgren-Lawrence grade（1-2）（all P < 0.05）. P value for heterogeneity test was 0.01 in different gender group. Conclusion：The results indicate that potential functional genetic variation in MAPK/ERK plays an important role in the pathogenesis of knee osteoarthritis.