Background Preoperative identification of patients at risk for severe operative difficulty during laparoscopic cholecystectomy remains clinically relevant. C-reactive protein (CRP) reflects systemic inflammatory burden and may predict intraoperative severity. This study evaluated the independent association between preoperative CRP levels and severe operative difficulty, and explored its performance in elective and emergency settings.Methods A retrospective cohort study of 304 patients undergoing laparoscopic cholecystectomy was performed. Severe operative difficulty was defined as Parkland grade IV–V. Multivariable logistic regression was used to assess independent predictors of severe operative difficulty, adjusting for urgency status, age, and sex. Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC). Subgroup analyses were conducted for elective and emergency procedures.Results Severe operative difficulty occurred in 89 patients (29.3%). In multivariable analysis, preoperative CRP independently predicted severe operative difficulty (adjusted OR 1.06 per unit increase; 95% CI 1.04–1.09; p < 0.001). Emergency surgery (adjusted OR 3.46; 95% CI 1.92–6.21; p < 0.001) and male sex (adjusted OR 2.20; 95% CI 1.20–4.03; p = 0.011) were also independently associated. The multivariable model demonstrated good discrimination (AUC 0.82). CRP performance was more pronounced in emergency procedures compared to elective cases. Severe operative difficulty was significantly associated with increased postoperative complications and prolonged hospital stay.Conclusions Preoperative CRP independently identifies patients at risk for severe operative difficulty during laparoscopic cholecystectomy. Its predictive value is particularly relevant in emergency settings and may assist in preoperative risk stratification and operative planning.