Purpose: Proton pump inhibitor (PPI) use has been associated with serum gastrin elevations. Hypergastrinemia increases colorectal mucosa proliferation and has been associated with colorectal cancer (CRC) in humans. Our aim was to determine whether PPI use is associated with subsequent CRC risk. Methods: We performed a population based case-control study in North Jutland County, Denmark. Using diagnostic codes we identified incident cases of CRC from the National Hospital Discharge Register. Using incidence density sampling we selected approximately ten controls from the Civil Registration System for each case matched on gender and birth year. Proton pump inhibitor use was measured by the number of prescriptions filled prior to CRC diagnosis and drawn from the Pharmaco-Epidemiological Prescription Database. Odds ratios for CRC were calculated for varying categories of PPI use using conditional logistic regression adjusted for relevant factors including NSAID use. Results: From 1991 through 2003, 4231 cases of CRC were identified and were compared to 42139 matched controls. Odds ratios were slightly increased in all prescription ranges of PPI use, however; only use in the 11–20-prescription range was significantly associated with CRC (adjusted OR = 1.44 (1.03, 2.03)). More importantly, there was no trend of increased risk across categories (p= 0.08). Nor were those in the highest use category (> 20 prescriptions) at significant risk for CRC (adjusted OR = 1.13 (0.80, 1.61)). Conclusions: While gastrin may be an important factor in the pathogenesis of some colorectal cancers, our study suggests that this does not translate into significant clinical risk for most PPI users.Table: Categorical Analysis of PPI Use and CRC.