Background and Aims Percutaneous transhepatic gallbladder drainage (PTGD) followed by elective laparoscopic cholecystectomy (LC) is a commonly used modality for the treatment of acute cholecystitis (AC). It is found in clinical practice that the time interval between PTGD and LC (PTGD-LC interval) would affect the degree of difficulty in performing LC, but the optimal time interval between the two procedures is still an unresolved question. Therefore, this study was performed to investigate the optimal timing of LC after emergency PTGD for AC patients, so as to provide guidance for clinical practice.Methods The clinical data of AC patients undergoing PTGD followed by elective LC in Shengjing Hospital of China Medical University from 2013 to 2019 were collected. According to the degree of difficulty of LC, the patients were classified into non-difficult group and difficult group, and the differences in PTGD-LC interval and other clinical variables between the two groups were compared. The ROC curve for PTGD-LC interval predicting difficult LC was drawn to obtain the cut-off value, and the fitted curve analysis with the PTGD-LC interval as independent variable and the proportion of cases of difficult LC as dependent variable was created to analyze the relationship between PTGD-LC interval and the difficulty of LC.Results A total of 98 patients were enrolled, with 56 cases in non-difficult group and 42 cases in difficult group. The PTGD-LC interval in non-difficult group was significantly longer than that in difficult group (69.0 d vs. 39.5 d, P=0.043), and in addition, the operative time for LC was significantly shorter and the aminotransferase levels were significantly lower in non-difficult group than those in difficult group (all P<0.05). The AUC of the ROC curve for PTGD-LC interval predicting difficult LC was 0.6, and the cut-off value was 40.5 d. The proportion of cases of difficult LC was significantly decreased when the interval was more than 40.5 d (30.8% vs. 66.7%, P=0.001), and meanwhile, the proportion of cases with severe pericholecystic adhesions and length of postoperative hospital stay were significantly reduced (both P<0.05). The fitted curve analysis showed that the proportion of cases of difficult LC reached the highest level at 15.1 d of PTGD-LC interval, followed by a continuous decrease, and then reached the lowest level at 61.7 d of PTGD-LC interval, followed by an increasing trend in later period.Conclusion The PTGD-LC interval is closely associated with the degree of difficulty of the elective LC. Taking both surgical difficulty and patients' quality of life into account, the optimal time interval of the elective LC after PTGD ranges from 40.5 to 61.7 d.