Background: Alkaline phosphatase (ALP) is a widely used marker for skeletal and hepatobiliary disorders, but its activity is also increased in atherosclerosis and peripheral vascular disease. It is an inflammatory marker like C-reactive protein (CRP). We therefore analyzed its relationship with CRP in the United States National Health and Nutrition Examination Survey (NHANES) 2005–2006. Methods: The analysis included 4155 men and non-pregnant women over the age of 20 years. The relationship between log-transformed ALP and plasma CRP was analyzed using univariate and multivariate models. Results: ALP activity was significantly correlated with age, waist circumference, body mass index, blood pressure, exercise, alcohol, triglycerides, and other liver enzymes after adjusting for age, gender and ethnicity (p<0.001). ALP was significantly associated with a higher frequency of cardiovascular disease (p=0.02), hypertension (p=0.01) hypercholesterolemia (p=0.04), and diabetes (p=0.02). Compared to the lowest quartile of ALP, the adjusted odds ratio (OR) associated with the highest quartile were 1.9 [95% confidence intervals (CI) 1.1–3.5], 1.6 (95% CI 1.0–2.5), 1.5 (95% CI 1.1–2.1) and 1.7 (95% CI 1.0–2.4) for cardiovascular disease, hypertension, hypercholesterolemia, and diabetes, respectively. In multivariate analysis, log ALP was an independent predictor of log CRP (p=1.0×10 −6 ). A multivariate model that included log ALP, ethnicity, glycohemoglobin, waist circumference, albumin, apolipoprotein B, γ-glutamyltransferase and uric acid explained 40% of the variance in log CRP. Conclusions: ALP is a marker of cardiometabolic risk, but it needs to be tested as part of a multivariate model in prospective studies. Clin Chem Lab Med 2010;48:167–73.