Fecal occult blood tests (FOBTs) are validated only for colorectal cancer (CRC) screening, but are commonly used as a diagnostic test in other clinical settings. We performed a systematic review to assess performance characteristics of FOBT as a diagnostic test for clinical indications.Bibliographic databases were searched to identify studies in adult patients with a specific gastrointestinal symptom or condition who underwent FOBT and a reference test and provided data on diagnoses. Our primary end point was sensitivity. Risk of bias was assessed with the QUADAS-2 tool.Twenty-two studies met the inclusion criteria: 12 in iron deficiency anemia (IDA) (5 fecal immunochemical (FIT) and 7 guaiac based), 8 in ulcerative colitis (FIT), and 2 in acute diarrhea (guaiac based). Only 2 studies had low risk of bias on all domains of the QUADAS-2. On meta-analysis, FOBT had a sensitivity of 0.58 (95% confidence interval [CI] 0.53-0.63) and a specificity of 0.84 (95% CI 0.75-0.89) in predicting presumptive causes of IDA at endoscopy, with comparable results for guaiac-based tests and FIT. Sensitivity was higher for CRC (0.83) than non-CRC lesions (0.54). FIT had a sensitivity of 0.72 (95% CI 0.57-0.84) and a specificity of 0.80 (95% CI 0.67-0.89) in predicting endoscopic activity in UC. Sensitivities of FOBT for positive stool culture in acute diarrhea were 0.38 and 0.87.Sensitivity of FOBT is poor for IDA: 42% of patients with identifiable causes of IDA had false-negative FOBT. Our results did not show acceptable performance characteristics for FOBT to guide decisions regarding endoscopic evaluation and do not support its use in IDA.