A profound number of prophylactic antibiotics are used after radical cystectomy with an ileal orthotopic neobladder (RCIONB) despite a negative effect of infection control. We investigated the impact of short-term prophylactic antibiotic use on infectious complications after RCIONB.We retrospectively reviewed data from 287 patients who underwent RCIONB for bladder cancer between 2012 and 2016 at a tertiary hospital. The patients were divided into 2 groups according to the pattern of prophylactic antibiotics (185 patients in a long-term group, 25-day use of 3-staged multiple antibiotics versus 102 patients in a short-term group, 24-hour use of cefotetan). The onset of complications, including bacteriuria, febrile urinary tract infection (FU), and bacteremia, and the microorganisms responsible for infections were compared between the groups. Of all 287 patients, bacteriuria, FU, and bacteremia were identified in 177 (61.7%), 85 (29.6%), and 18 (6.3%) patients, respectively. Bacteriuria was identified more frequently in the short-term group (49.2% vs 84.3%, P <.001). However, the rates of FU within 60 days of surgery were similar in both groups (28.6% vs 28.4%, P = .969). The rate of FU was not significantly different between the 2 groups. There was no significant difference in the rate of patients with bacteremia (5.4% vs 7.8%, P = .415). The most frequent microorganisms seen in bacteriuria were Enterococcus faecium and Enterococcus faecalis, in the long-term and short-term group, respectively. Antibiotic-resistant Enterococcus species were more frequently present in the long-term group.Short-term use of prophylactic antibiotics is effective for preventing urinary tract infections after RCIONB and decreasing colonization with multi-drug-resistant organisms.