PURPOSE: Intraoperative floppy iris syndrome (IFIS) is associated with an increased rate of severe intraoperative complications and greater visual morbidity during cataract surgery, particularly in females. To date, no post-marketing pharmacovigilance study has comprehensively examined all FDA-approved drugs for their association with IFIS development or explored potential sex differences. Understanding the risk factors for IFIS allows cataract surgeons to better stratify surgical risks and implement appropriate preoperative and intraoperative measures to ensure adequate pupil dilation in high-risk patients. DESIGN: Retrospective pharmacovigilance clinical cohort study. METHODS: This population-based, observational study analyzed IFIS cases reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) from October 2003 to March 2024 using OpenVigil 2.1. Disproportionality metrics, including reporting odds ratios (RORs), proportional reporting ratios (PRRs), and relative risk reductions (RRRs), were used to assess signals for positive adverse reactions (n>
2, χ²>
4, PRR>
2), compared to all other drugs. Subgroup analyses were also conducted by sex. RESULTS: Of 12,345,128 adverse event (AE) reports, 649 (0.0053%) involved IFIS. The majority of cases were reported by healthcare professionals (75.75%, n=203), followed by consumers (12.69%, n=34) and unknown sources (11.57%, n=31). Drugs with the highest disproportionality for IFIS included imipramine (ROR=251.66, 95% CI=157.53-402.02), tamsulosin (ROR=171.44, 95% CI=143.12-205.36), and chlorpromazine (ROR=91.30, 95% CI=49.91-167.03) (all p<
0.0001, IC CONCLUSIONS: This analysis of over 20,000 drugs and 12 million reports highlights that, in addition to α1-blockers and atypical antipsychotics, tricyclic antidepressants are among the key agents most disproportionately associated with IFIS, with notable sex differences. These findings are crucial for informing perioperative counseling and surgical planning for cataract surgery.