Background Ondansetron is an antiemetic drug (AED) used to prevent and treat nausea and vomiting. The summary of product characteristics reports a rare risk of transient blindness primarily during IV injections, notably with the concomitant use of chemotherapeutic agents. We aimed to refine the characterization of ondansetron-induced blindness. Research design and methods We performed a descriptive and a case/non-case analysis using VigiBase®. Cases were defined as reports of adverse drug reactions (ADRs) related to blindness: amaurosis, amaurosis fugax, blindness. Non-cases were all other recorded reactions. Reporting risk of blindness-related ADRs was assessed using a disproportionality analysis and expressed as Reporting Odds Ratios (ROR). Results 138,315 ADRs were reported with AEDs, including 136 blindness-related ADRs, among them 44 (32.4%) with ondansetron. For ondansetron users, blindness-related ADRs occurred mainly on the first day. Out of the 25 patients with known outcomes, 18 (72.0%) were recovering or had recovered, 7 (28.0%) patients had not recovered There were no statistical differences in the number of cases for IV or oral users and for users or not of chemotherapeutic agents. Compared with other AEDs, ondansetron was associated with an increase in the reporting risk of blindness-related ADRs (ROR = 4.00 [2.79–5.72], p < 0.001). Conclusions Rarely blindness can occur following intravenous or oral administration of ondansetron.