Introduction: Rectal budesonide foam, a second-generation corticosteroid with high first-pass hepatic metabolism, is indicated for induction of remission of mild to moderate distal ulcerative colitis (UC). This study prospectively assessed long-term tolerability of cyclically dosed budesonide foam. Methods: Adults with active distal UC (ulcerative proctitis or ulcerative proctosigmoiditis extending ≤40 cm from the anal verge) who previously participated in budesonide foam clinical trials received 6-week cycles of open-label budesonide foam: 2 mg/25 mL twice daily (BID) for 2 weeks, then once daily (QD) for 4 weeks as needed to manage disease flares. Cycles were separated by ≥48 hours. Safety assessments included periodic fasting blood chemistries, serum cortisol levels, and recording of adverse events (AEs) through 1 week post-treatment. Results: 114 patients received cycle 1, 65 cycle 2, and 41, 22, 12, 5, 3, and 1 patient received cycles 3-8, respectively. The mean duration of exposure for all patients was 92 days (range, 10-335 days). At baseline, mean modified Mayo Disease Activity Index [MMDAI] score was 7.2; 57.9% of patients had moderate distal UC (MMDAI score, 7-10). Mean treatment compliance was ≥90.5% for all 8 treatment cycles. Overall, 57.9% of patients had AEs, the most frequent of which were decreased blood cortisol concentration (17.5% [11.4% considered drug-related]), abdominal pain (7.9%), and headache (7.0%). Most AEs (experienced by 90.9% of patients) were mild or moderate in intensity, and their frequency was similar across cycles with the largest populations (cycle 1 [43.0%], 2 [43.1%], and 3 [41.5%]). No serious AEs were observed. Of the 17 patients (14.9%) who withdrew from the study because of an AE, 8 (7.0%) withdrew due to decreased blood cortisol concentrations. Mean morning serum cortisol concentrations decreased from baseline to day 15 (end of BID dosing; range, -87.8 to -25.5 nmol/L), but recovered at week 6 (end of QD dosing; range, -10.4 to 0.9 nmol/L), during cycles with >15 patients (cycles 1-4). Normal (≥138 nmol/L) morning serum cortisol concentrations were observed in ≥75% of patients at day 15 and ≥83.9% at week 6 for all treatment cycles. No clinically relevant changes in vital signs and physical exam findings were observed. Conclusion: Multiple repeat treatments with cyclically dosed rectal budesonide foam were well tolerated by patients with distal UC flares. Funded by Salix Pharmaceuticals.