Prompt antimicrobial therapy, together with subsequent biliary drainage, is crucial to prevent the rapidly deteriorating course of severe acute cholangitis. Therefore, updates in bacteriological epidemiology and resistance profile are important for management of this critical disease. Also, because the routine addition of metronidazole to the first-line regimen is controversial, we intended this prospective study with historical controls. Patients with severe acute cholangitis who fulfilled the definition of severity by the Tokyo Guidelines and underwent biliary drainage within 24 h from presentation were enrolled prospectively from January 2010 to December 2011. During that period, metronidazole was not added to third-generation cephalosporins, which were used as the initial antimicrobials except for patients who were allergic to penicillin and received ciprofloxacin instead (no metronidazole group). Outcomes were compared with a historical cohort from March 2007 to December 2009 when metronidazole was added routinely (metronidazole group). A unified strategy was maintained throughout the whole period excepting the use of metronidazole. Outcomes between the metronidazole group (n = 338) and the no metronidazole group (n = 338) did not differ in terms of the rate of successful biliary drainage by interventional procedures (93.2% vs. 94.7%, p = 0.88), time elapsed for cholangitis to be controlled (10.4 ± 0.6 vs. 8.9 ± 1.2 days, p = 0.38), and mortality (1.2% vs. 0.6% with p = 0.34 for all causes and 0.9% vs. 0% with p = 0.15 for cholangitis-related, respectively). As the routine addition of metronidazole did not improve outcomes, it can be excluded from the first-line regimen if emergent biliary drainage can be performed efficiently.