Abstract Background The intraindividual variability of C-reactive protein (CRP) remains uncertain. Although guidelines suggest stability of serial CRP values comparable to that of cholesterol measures, several studies indicate greater fluctuations of CRP. We sought to compare the intraindividual variability of CRP with that of cholesterol measures using the multi-ethnic study of atherosclerosis (MESA). Methods CRP measurements were available in 760 MESA participants after exclusion of those with comorbidities or medications known to affect CRP or CRP≥10 mg/L. Serial values were available for 255 participants. The intraclass correlation coefficient (ICC) was quantified for CRP, total cholesterol (TC), and non-HDL-cholesterol (non-HDL-C) as the ratio of between-subject variance to the sum of between-subject and within-subject variance. Fluctuation between baseline and follow-up categories was calculated by cross-classifying participants according to baseline tertiles. Results The multivariable-adjusted ICC of CRP was 0.62 (95% CI, 0.55–0.68), significantly lower than that of TC (0.75; 95% CI, 0.70–0.81; p = 0.001 vs CRP) and non-HDL-C (0.76; 95% CI, 0.71–0.81; p = 0.001 vs CRP). 51% of participants in the highest baseline CRP tertile had discordant values on follow-up, while 54% and 27% were discordant in the middle and lowest baseline CRP tertiles. Among participants with baseline CRP levels exceeding 3 mg/L, a clinical threshold for higher risk, 69% had subsequent measurements falling within a lower risk category. Conclusions In the MESA cohort, intraindividual variation of CRP was significantly greater than that for cholesterol measures. Our results suggest that further evaluation of CRP variability is needed in large prospective studies using shorter intervals between measurements.