Difficult laparoscopic cholecystectomy (DLC) may increase the risk of complications and extend the duration of hospitalization. The aims of this study were to evaluate the predictive value of C-reactive protein/albumin ratio (CAR) for DLC in patients with acute cholecystitis (AC) diagnosed according to the Tokyo Guidelines 2018 and to develop a preoperative predictive model for DLC. We retrospectively analyzed 205 patients who had laparoscopic cholecystectomy for AC between January 2012 and December 2020. We defined DLC cases as having one of the following factors: blood loss ≥50 mL, operative time ≥150 minutes, or conversion to open surgery. We classified the remaining cases into the non-DLC group. Overall, 127 (62.0%) and 78 (38.0%) patients were grouped into the DLC and non-DLC groups, respectively. Patients in the DLC group had: higher severity grade, which was assessed using the Tokyo Guidelines 2018; higher incidence of postoperative complications; and more hospitalization days than those in the non-DLC group. Multivariate analysis revealed that male, CAR (≥3.20), and pericholecystic fat hyperdensity on computed tomography (CT) were independent predictors of DLC. We developed a predictive scoring system for DLC based on these three factors (cutoff value, 2.0; area under the curve, 0.75; sensitivity, 71.7%; and specificity, 70.5%). CAR could predict DLC independently in AC patients. We identified male gender, CAR, and pericholecystic fat hyperdensity on CT as predictive factors for DLC and established a preoperative prediction system based on these three factors.