Background <p>The optimal timing of laparoscopic cholecystectomy (LC) after percutaneous transhepatic gallbladder drainage (PTGBD) for acute cholecystitis remains controversial. Previous studies have often categorized surgical timing using arbitrary cutoffs and have not adequately evaluated potential non-linear associations. In particular, the interval from PTGBD to LC has rarely been analyzed as a continuous variable when assessing operative difficulty. This study aimed to assess the relationship between the interval from PTGBD to LC and intraoperative technical difficulty using restricted cubic spline (RCS) analysis.</p> Methods <p>This retrospective single-center study included patients with acute cholecystitis who underwent LC after PTGBD between November 2014 and November 2024. The primary outcome was bailout surgery (conversion to open surgery, subtotal cholecystectomy, or fundus-first approach). Secondary outcomes included operative time, intraoperative blood loss, postoperative length of stay, and major postoperative complications (Clavien–Dindo ≥ III). The interval from PTGBD to LC was analyzed as a continuous variable using multivariable regression models incorporating RCS. Models were adjusted for age, C-reactive protein (CRP) at diagnosis, Tokyo Guidelines 2018 severity grade, previous abdominal surgery, anticoagulant therapy, and Charlson Comorbidity Index.</p> Results <p>A total of 257 patients were included, of whom 94 (36.6%) required bailout surgery. RCS analysis demonstrated no significant association between the PTGBD to LC interval and the probability of bailout surgery (overall <i>p</i> = 0.3824; non-linear <i>p</i> = 0.6201), and no clear temporal threshold associated with reduced operative difficulty was identified. In multivariable analysis, higher CRP at diagnosis was independently associated with bailout surgery (adjusted odds ratio 1.033, 95% CI 1.006–1.062). The interval from PTGBD to LC was not independently associated with operative time, intraoperative blood loss, or major postoperative complications. A small statistical association was observed with postoperative length of stay; however, the magnitude of this effect was minimal.</p> Conclusions <p>When analyzed as a continuous variable using RCS modeling, the interval from PTGBD to LC was not independently associated with the risk of bailout surgery, and no optimal timing threshold was identified within the observed range of this real-world cohort. These findings suggest that operative difficulty after PTGBD may be influenced more by the inflammatory burden at diagnosis than by elapsed time alone, supporting an individualized approach to surgical timing.</p>