Background: Failure of hypertension treatment is a major clinical issue because of the high prevalence and the associated mortality risk. We have reported evidence that creatine kinase increases blood pressure through greater sodium retention and cardiovascular contractility, by rapidly providing ATP for these functions. Therefore, we hypothesized that high creatine kinase is associated with failure of antihypertensive treatment. Method: We analyzed a cross-sectional, random multiethnic sample of the general population (N ¼ 1444), aged 34–60 years. The primary outcome was the independent association between resting serum creatine kinase and treated uncontrolled hypertension in the population, using multinomial logistic regression analysis. Results: Hypertension prevalence was, respectively, 26.8; 30.8; and 41.2% for the lowest (<88 IU/l) through the highest population creatine kinase tertile (>145 IU/l; P < 0.001). Treatment failed in 72.9% of participants within the highest creatine kinase tertile vs. 46.7% within the lowest tertile (P ¼ 0.004). In logistic regression analysis, creatine kinase was the main predictor of treatment failure (adjusted odds ratio 3.7; 95% confidence interval 1.2–10.9), independent of age, sex, BMI, fasting glucose, ethnicity, or education level. Conclusion: Creatine kinase is associated with failure of antihypertensive therapy. Further investigations concerning this association might help improve treatment strategies for difficult-to-treat hypertension. Abbreviations: ANOVA, one-way analysis of variance; cGMP, guanosine cyclic 3 0 ,5 0-(hydrogen phosphate); CI, confidence interval; Mg, magnesium; MLCP, myosin light chain phosphatase; SER, sarcoendoplasmic reticulum BACKGROUND