C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that isassociated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ~25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency 5 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10-6). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10-15). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-∈2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10-8), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In genebased tests, a burden of rare/lower frequency variation inCRPin EAs (P ≤ 6.8 × 10-4) and in retinoic acid receptor-related orphan receptor a (RORA) in AAs (P = 1.7 × 10-3) were associated with CRP levels at the candidate gene level (P < 2.0 × 10-3). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.