C-reactive protein (CRP) is a well-known biomarker of systemic inflammation and cardiovascular disease. We investigated the trends in prevalence of elevated CRP levels (>3.0 mg/L) in a general population of US adults. Data from 27,214 subjects aged ≥20 years in the 1999-2010 National Health and Nutrition Examination Survey were analyzed. After adjustment for age, sex, race/ethnicity, body mass index (weight (kg)/height (m)(2)), and medications for lowering blood pressure, glucose, and lipids, the prevalence of elevated CRP decreased significantly from 36.7% in 1999-2002 to 32.0% in 2007-2010, corresponding to a decrease in mean CRP level from 1.92 to 1.66 mg/L (both P < 0.001). The trend remained significant after additional adjustment for several traditional cardiovascular risk factors and use of different medications, including statins. However, the decreasing trends were attenuated after additional adjustment for total bilirubin (P = 0.08 and 0.02), which increased from 0.62 to 0.73 mg/dL over 12 years (P < 0.001). The decreasing trend of CRP levels is encouraging and may be related to the increase in total bilirubin levels. Such trends may be explained in part by the increasing use of medications such as statins, which can increase bilirubin levels and decrease CRP levels.