The objective of this study was to determine the risk for cysto-biliary fistula (CBF) and preoperative predictive factors in patients with hepatic hydatid disease (HHD) with high levels of hepatobiliary enzymes (HLE) alone. The risk of CBF and predictive factors in patients with HHD whose only sign of fistula was HLE is unknown. A total of 116 patients without clinical and radiologic signs who were operated for HHD were categorized into 2 groups: patients with and without HLE. The patients with HLE were defined as "usual suspicious.'' The potential preoperatively predictive factors for CBF were retrospectively analyzed in this group. Our data included 18.1% of patients (n = 21) with CBF and 69.2% of patients (n = 81) with HLE. The usual suspicious group contained 24.7% of patients (n = 20) with CBF. The risk of CBF was 11-fold higher in the usual suspicious group (95% confidence interval, 1.4-86.7). The red cell distribution width (RDW) was higher in patients with CBF than in patients without CBF in the usual suspicious group (P = 0.006). The performance of the RDW, with a cutoff value of 13.75%, was found to be suboptimal for predicting CBF for patients in the usual suspicious group (area under the curve, 0.661; 95% confidence interval, 0.525-0.798). We defined a new preoperatively high-risk group with HLE alone; this definition can help to identify patients at risk for preoperatively undetectable CBF. The RDW was not found to be sufficient for the discrimination of usual suspicious group with CBF.