Helicobacter pylori infection is a strong risk factor for gastric cancer. A positive association with colorectal cancer has also been suggested, but available evidence remains inconclusive. In this population-based case-control study we investigated the association between H. pylori seroprevalence and colorectal adenocarcinoma under consideration of pro-inflammatory gene polymorphisms (384 incident cancer patients, 467 matched control subjects). Overall, the H. pylori seroprevalence was higher among cases (51%) than among controls (44%), and a positive association between H. pylori seroprevalence and colorectal adenocarcinoma risk was found, that persisted after adjustment for known potential confounders, including measures of socioeconomic status (odds ratio (OR)=1.41; 95% confidence intervals (CI), 1.06-1.87). Presence of specific H. pylori cytotoxin-associated gene A (CagA) antibodies did not significantly affect the observed risk. Additionally, a pro-inflammatory genotype did not increase the colorectal cancer risk associated with H. pylori infection. H. pylori positive subjects carrying the pro-inflammatory genotypes even had a lower risk.