Uncovering a dose-response relationship between positive fecal immunochemical test (FIT) and all-cause, cardiovascular and cancer-related mortality

•Fecal immunochemical test (FIT) was used for colorectal cancer (CRC) screening. Positive FIT was referred for colonoscopy to identify CRC or adenomas and, so far, provided no other health implications.•Positive FIT (≥20 μg Hb/g) was associated with increased mortalities from all causes, all cancers, and cardiovascular disease (CVD).•One-year loss of life or a 4 % increase in all-cause mortality was observed for every 10 μg Hb/g increase above 20 μg Hb/g, even with CRC deaths excluded, indicating the presence of a dose-response relationship.•Nearly 1/5 (18.6 %) of deaths among subjects with positive FIT were attributed to CVD, followed by CRC (13.5 %) and upper gastrointestinal (GI) cancers (4.5 %).•Strategies to mitigate the increased mortality risks of individuals with positive FIT after negative colonoscopy include a workup on reducing risks from CVD and ruling out upper GI cancers by gastroscopy. Fecal immunochemical test (FIT) is for colorectal cancer (CRC) screening. Its association with non-CRC mortality has been overlooked. Given the quantitative FIT values, its dose-response relationships with different causes of deaths and years of life shortened were assessed. This retrospective study included 546,214 adults aged ≥ 20 who attended a health surveillance program from 1994 to 2017 and were followed up until the end of 2020. FIT ≥ 20 μg Hb/g was defined as positive. The Cox model was used to assess adjusted hazard ratios (aHR). Positive FIT was associated with increased all-cause mortality (aHR: 1.34, 95 % CI: 1.25–1.44) and all-cancer mortality (aHR: 1.71, 95 % CI: 1.55-1.89), with a reduction of life expectancy by 4 years. The association remained even with CRC excluded. With each 10 μg Hb/g increase in FIT above 20 μg Hb/g, life expectancy was reduced by one year, and mortality increased by 4 %. About 18.6 % of deaths with positive FIT were attributed to cardiovascular disease (CVD), followed by CRC (13.5 %) and upper gastrointestinal (GI) cancers (4.5 %). The all-cause mortality rate after excluding CRC for positive FIT was 3.56/1,000 person-year, comparable to the all-cause mortality rate of 3.69/1,000 person-year for hypertension. Positive FIT was associated with increased mortality in a dose-response manner and shortened life expectancy by 4 years, an overlooked risk comparable to hypertension, even with CRC excluded. After a negative colonoscopy, subjects with positive FIT should undergo a workup on CVD risk factors and look for other upper