Background Roflumilast is an add-on therapy for COPD following exacerbations, but real-world safety data in the U.S. is limited. Objective This study aimed to identify safety signals associated with roflumilast use through a high-throughput signal detection algorithm. Methods Using sequence symmetry analysis (SSA), we analyzed Marketscan databases for new roflumilast users (2011–2021). We screened for adverse effects across 211 therapeutic classes within 365 days of initiation. Sensitivity analyses were conducted by sex, age, and observation period. Crude and adjusted sequence ratios (cSR, aSR) were reported with 95% confidence intervals (CIs). Results Among 11,091 patients (53% aged 65+, 52% female), 19 safety signals were identified. Strong associations were observed with anti-thyroid agents (aSR, 3.62; 95% CI: 1.44–10.36), parathyroid hormones (aSR, 2.65; 95% CI: 1.33–5.51), and meglitinides (aSR, 2.43; 95% CI: 1.15–5.35). While many signals aligned with prior clinical trial data, novel associations with anti-thyroid and parathyroid agents were discovered. Conclusion In our study, we detected 19 safety signals for roflumilast, including notable associations with anti-thyroid agents and parathyroid hormones. Future investigations using more robust study designs are warranted to evaluate those signals.