Systemic antihistamines were administered prior to dye injection in 50 patients undergoing fluorescein angiography. The patients were monitored for side effects. Venous blood samples were obtained before and at three, ten and thirty minutes after intravenous administration of sodium fluorescein and analyzed for histamine levels. Three patients (6%) developed minor side effects of nausea or dizziness; this compares to an incidence of 21% in a previous series of patients from our institution untreated with antihistamines. A three-fold increase in plasma histamine levels occurred in 28% of patients following fluorescein and antihistamine injection; this compares with a 26% incidence of increase in plasma histamine in patients receiving fluorescein without antihistamines (as determined in a previous study). Prophylactic antihistamines should be considered in patients undergoing fluorescein angiography if they have a history of previous allergies or side reactions during prior fluorescein studies. However, complete prophylaxis against severe side reactions to fluorescein injections is not assured with antihistamines.