Chronic inflammation, which is suspected to play a role in the development of colorectal cancer (CRC), has rarely been studied in colorectal adenoma. We investigated the inter-relationships of serum levels of the inflammatory proteins CRP and in IL-6, single nucleotide polymorphisms (SNPs) in the CRP (rs1205, rs1130864, rs1800947) and IL6 (rs1800795) genes, and lifestyle factors with colorectal adenoma in a sigmoidoscopy-based case-control study of 271 adenoma cases and 539 age-, sex-, and race/ethnicity-matched controls in Hawaii. We found no association of serum CRP or IL-6 levels with the risk of adenoma. A multiple regression with stepwise selection identified elevated BMI, Caucasian and Native Hawaiian versus Japanese race/ethnicity, and current smoking as being associated with significantly higher serum CRP and IL-6 levels. Female versus male gender was also associated with higher CRP levels and older age with higher IL-6 levels. The C allele of rs1205 and the A allele of rs1130864 were significantly associated with higher serum CRP levels (p (trend): 0.0002 and 0.01, respectively), as well as with a decreased adenoma risk [rs1205: OR for CT and CC vs. TT = 0.69 (95% CI: 0.48-0.98) and 0.53 (0.34-0.83), respectively, p (trend) = 0.008; rs1130864: OR for GA and AA versus GG = 0.65 (0.45-0.93) and 0.74 (0.31-1.76), respectively, p (trend) = 0.04]. The findings of lower serum CRP and IL-6 levels in Japanese (a group with a high CRC risk) and of a decreased adenoma risk observed for alleles associated with higher circulating CRP levels suggest a protective effect for CRP in early colorectal neoplasia that warrants further study.