White blood cell levels (WBC) is the only biologic determinant criterion of the severity assessment of acute cholecystitis (AC) in the revised Tokyo Guidelines 2018 (TG18). The aims of this study were to evaluate the discriminative powers of common inflammatory markers (neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP)) compared with WBC for the severity of AC, and the risk for conversion to open surgery and to determine their diagnostic cutoff levels. This was a prospective cohort study. Over 3 years, 556 patients underwent laparoscopic cholecystectomy for AC. Patients were classified into two groups: 139 cases of advanced acute cholecystitis (AAC) (gangrenous cholecystitis, pericholecystic abscess, hepatic abscess, biliary peritonitis, emphysematous cholecystitis), and 417 cases of non-advanced acute cholecystitis (NAAC). Multiple logistic regression and receiver-operating characteristic curve analysis were employed to explore which variables (WBC, CRP, and neutrophil-to-lymphocyte ratio (NLR)) were statistically significant in predicting AAC and conversion to open surgery. On multivariable logistic regression analysis, male gender (OR = 0.4; p = 0.05), diabetes mellitus (OR = 7.8; p = 0.005), 3–4 ASA score (OR = 5.34; p = 0.037), body temperature (OR = 2.65; p = 0.014), and CRP (OR = 1.01; p = 0.0001) were associated independently with AAC. The value of the area under the curve (AUC) of the CRP (0.75) was higher than that of WBC (0.67) and NLR (0.62) for diagnosing AAC. CRP was the only predictive factor of conversion in multivariate analysis (OR = 1.008 [1.003–1.013]. Comparing areas under the receiver operating characteristic curves, it was the CRP that had the highest discriminative power in terms of conversion. CRP is the best inflammatory marker predictive of AAC and of conversion to open surgery. We think that our results would support a multicenter—international study to confirm the findings, and if supported, CRP should be considered as a severity criterion of acute cholecystitis in the next revised version of the Guidelines of Tokyo.