Background <p>Malignancy remains one of the major differentials for bile duct strictures (BDS). Endoscopic sampling of the BDS provides low and variable sensitivity, often reporting “atypical” or “suspicious” cytology results in accordance with Papanicolaou criteria. We sought to perform a systematic review investigating the risk of malignancy for initially indeterminate cytology to aid in preoperative patient counseling.</p> Patients and Methods <p>A comprehensive search of databases including Scopus, EMBASE, and PubMed, was performed between each database’s inception and 8 July 2024. Observational studies confirming malignancy rates in patients with atypical and/or suspicious bile duct cytology upon initial endoscopic brush cytology were included. Two reviewers independently screened articles and extracted data. Of 4159 articles initially identified, 144 were examined in full-text review and 46 were deemed eligible for inclusion.</p> Results <p>Of 8458 total samples, 2826 (33.3%) samples had indeterminate brush cytology, consisting of either atypical (<i>n</i> = 1902) or suspicious (<i>n</i> = 924) brushings. Malignancy risk in samples with atypical and suspicious brush cytology was 50.4% and 80.2%, respectively. Suspicious cytology was associated with a relative risk of 1.59 for malignancy relative to atypical cytology. There was a 60.1% risk of malignancy among all samples with indeterminate brush cytology.</p> Conclusions <p>Our study provides pooled estimates of risk of malignancy in patients with bile duct strictures and indeterminate cytology. This is one of the first meta-analyses on the topic. Our findings can be used by physicians for preoperative counseling of patients being worked up surgically for biliary strictures with indeterminate cytology.</p>