Background. Clostridium difficile infection (CDI) is the most common nosocomial infection, and is increasing. The major risk for CDI is antibiotic (abx) use. We have previously shown that secondary prophylaxis with vancomycin decreases CDI relapse in patients with recent CDI given abx to treat another infection. The median time to relapse after use of abx was 3 days. In an effort to further elucidate the best way to employ secondary prophylaxis against CDI, we examined all patients with CDI in our institution in 2016 and timing of relapse as related to another exposure to abx and the success of prophylaxis relative to the timing and the duration of prophylaxis. Methods. All patients positive by PCR for C difficile at our institution in 2016 were examined for receipt of abx within 3 months of a positive PCR. The relapse rates for all patients, patients who received abx with or without secondary prophylaxis, and patients who did not receive abx were calculated. Timing of the relapse from the prior CDI and from receipt of abx were determined as was impact of prophylaxis, particularly in patients who relapsed despite prophylaxis. Results. 1748 patients were identified, representing 2181 episodes of CDI. The relapse rates and timing based on prior CDI, receipt of additional abx prior to relapse, and use of prophylaxis are shown in Table 1. Prophylaxis decreased the overall relapse rate from 19.2% to 11.6%. Time to relapse in patients who relapsed despite prophylaxis was significantly longer indicating prophylaxis was having an effect. The failure appears dependent on when prophylaxis was started relative to abx and how long prophylaxis was given relative to abx. Conclusion. Prophylaxis is effective in preventing relapses in patients given abx after CDI however the timing and duration of prophylaxis significantly impacts the effectiveness. The majority of CDI relapses after abx occur within 3 days and can be prevented by prophylaxis. Relapses that occur after 3 weeks appear unrelated to the use of abx and are not preventable through prophylaxis. Failures of prophylaxis within the first 1 week are likely related to starting prophylaxis too late after abx and failures that occur between 1 and 3 weeks after abx are likely related to ending prophylaxis too early