Proton-pump inhibitors are associated with a high false-positivity rate in faecal immunochemical testing

False-positivity rates in faecal immunochemical test (FIT) can be affected by drug exposure. We aimed to assess the association between proton pump inhibitors (PPI) consumption and false positive (FP) results in a colorectal cancer (CRC) screening programme using electronic prescription records. A retrospective cohort study within a population-based screening program for CRC from 2010 to 2016 was performed. Participants with a conclusive FIT result and with prescription electronic data were included. An FP result was defined as having a positive FIT (≥ 20 µg haemoglobin/g faeces) and a follow-up colonoscopy without intermediate or high-risk lesions or CRC. Screening data were anonymously linked to the public data analysis program for health research and innovation (PADRIS) database that recorded patient diseases history and reimbursed medication. PPI exposure was defined as having retrieved at least one dispensation of PPI three months prior to the FIT. A total of 89,199 tests (of 46,783 participants) were analysed, 4824 (5.4%) tested positive and the proportion of FP was 53.5%. Overall, 17,544 participants (19.7%) were PPI users prior to FIT performance. PPI exposure increased the probability of obtaining an FP FIT result from 50.4 to 63.3% (adjusted OR 1.39; 95% CI 1.18–1.65). Nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, antibiotics, and laxatives were also associated with an FP result. The effect of PPI was independent and showed a synergistic interaction with nonsteroidal anti-inflammatory drugs. PPIs increase FIT positivity at the expense of FP results. The recommendation to avoid their use before FIT performance could reduce up to 3% of colonoscopies and 9% of FP results.