Recurrent Clostridioides (Clostridium) difficile infection (rCDI) is common and increases healthcare resource utilization. In this study, we assessed rCDI risk factors using an up-to-date, Japanese national hospital-based database. C. difficile infection (CDI) episodes, occurring July 2014–June 2017, in patients aged ≥18 years were extracted from the database and a nested case-control analysis was performed. Cases were defined as rCDI episodes which required re-initiation of oral vancomycin or oral/intravenous metronidazole treatment within 8 weeks from the start of initial treatment. Cases were matched to 4 non-rCDI episodes at the timing of rCDI occurrence. Adjusted odds ratios (ORs) were estimated using multivariate conditional logistic regression model. Of 18,246 initial CDI episodes, 3250 (17.8%) had at least one rCDI. Approximately 90% of episodes occurred in inpatients and 65% were treated with metronidazole. Older age (<75 years vs 75–84 years and vs 85 + years) was associated with higher risk of rCDI (OR = 1.27, 95% confidence interval 1.15, 1.41 and 1.45 1.30, 1.61, respectively). Use of systemic antibiotics (3.16 2.90, 3.44), probiotics (2.53 2.32, 2.77), chemotherapy (1.28 1.08, 1.53), or proton pump inhibitors (PPIs) (1.17 1.07, 1.28), and prior CDI history (1.22 1.03, 1.43) were also identified as rCDI risk factors. Vancomycin reduced the risk of rCDI compared with metronidazole treatment (0.83 0.76, 0.91). This large, multicenter, nationwide study confirmed that older age, PPIs, antibiotics, probiotics, chemotherapy, and prior CDI history are risk factors for rCDI in Japan. There was a 17% decrease of rCDI risk with vancomycin vs metronidazole treatment. Clinical trial registration number: N/A.