PURPOSE: To compare the image quality and safety of ultra-widefield fluorescein angiography using 3 mL (300 mg) versus 1 mL (100 mg) of 10% fluorescein. METHODS: In this prospective, randomized clinical trial, a total of 144 patients who required ultra-widefield fluorescein angiography examination for various retinal diseases were randomized 1:1 to 300 mg or 100 mg of fluorescein. Images were qualitatively graded by three retinal specialists and quantitatively analyzed. The primary outcome measure was the assessment of image quality (scored in a five-point scale). Quantitative subanalysis among normal ultra-widefield fluorescein angiography images through pixel intensity in posterior and midperipheral zones was also performed. RESULTS: A total of 67 participants in each group were included in the analysis. The mean difference of image quality between two dose groups was within the predefined noninferiority margin of 0.5 (0.005
95% confidence interval, -0.145 to 0.154). The mean pixel intensity showed no significant differences in both posterior and midperipheral zones ( P = 0.988 and 0.726, respectively). In the safety analysis, significantly fewer adverse events were observed with the lower dose (300 mg, 10 of 67 [14.9%] vs. 100 mg, 3 of 67 [4.5%], P = 0.041). CONCLUSION: We demonstrated the noninferiority of image quality of low-dose fluorescein (100 mg) compared with a 300 mg dose with a reduction in the rate of adverse events associated with fluorescein angiography.