Recurrent Clostridioides difficile infection (rCDI) often occurs after standard-of-care antibiotics. VOWST oral spores (VOS, previously SER-109), an FDA-approved orally administered microbiome therapeutic, is indicated to prevent rCDI following antibiotics for rCDI. To evaluate safety and efficacy of VOS from two phase3 trials, (randomized, placebo-controlled [ECOSPORIII: NCT03183128] and open-label, single arm [ECOSPORIV: NCT03183141]) of 349 adults with rCDI and prevalent comorbidities. VOS or placebo [ECOSPORIII only] (4 capsules once daily for 3days). Integrated analysis of treatment-emergent adverse events (TEAEs) collected through week8; serious TEAEs and TEAEs of special interest collected through week24; and rates of rCDI (toxin-positive diarrhea requiring treatment) evaluated through weeks8 and 24. TEAEs were mostly mild or moderate and gastrointestinal. Most common treatment-related TEAEs were flatulence, abdominal pain and distension, fatigue, and diarrhea. There were 11 deaths (3.2%) and 48 patients (13.8%) with serious TEAEs, none treatment-related. The rCDI rate through week8 was 9.5% (95%CI 6.6-13.0) and remained low through 24weeks (15.2%; 95%CI 11.6-19.4). Safety and rCDI rates were consistent across subgroups including age, renal impairment/failure, diabetes, and immunocompromise/immunosuppression. VOS was well tolerated and rates of rCDI remained low through week24 including in those with comorbidities. These data support the potential benefit of VOS following antibiotics to prevent recurrence in high-risk patients. ClinicalTrials.gov identifier, NCT03183128 and NCT03183141.