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Purpose: To evaluate the usefulness of indocyanine green angiography (ICGA) to detect leaking spots and the effectiveness of ICGA-guided focal laser photocoagulation in eyes with diabetic macular edema (DME). Methods: Ten eyes (8 patients) with diffuse DME diagnosed using fluorescein angiography (FA) and refractory to a sub-Tenon injection of triamcinolone acetonide (STTA), grid laser photocoagulation, or both were enrolled. FA and ICGA were performed using the Heidelberg Retina Angiograph 2. Hyperfluorescent spots on early-phase FA and on early- and late-phase ICGA were superimposed onto the macular thickness map measured by optical coherence tomography (OCT) and counted to calculate the spot density in the area with or without macular edema (ME). ICGA-guided focal laser photocoagulation was carried out. In 7 eyes, STTA was simultaneously performed. The central macular thickness (CRT) and macular volume (MV) were measured by OCT. Results: On early-phase FA, 4.8 ± 2.3 and 2.3 ± 1.5 hyperfluorescent spots/disk area were observed inside and outside the ME, respectively. In contrast, the spot density was significantly decreased to 1.8 ± 0.9 inside the ME and was only 0.3 ± 0.4 outside the ME on late-phase ICGA (p < 0.01). The mean follow-up period after ICGA-guided photocoagulation was 19.0 months. The mean best-corrected visual acuity improved significantly from 0.77 ± 0.34 logarithm of the minimum angle of resolution at baseline to 0.52 ± 0.37 at the last visit (p < 0.01). Both CRT and MV significantly decreased (p < 0.01). Recurrence of DME was observed in 4 eyes: 3 eyes were treatable only with STTA and 1 required additional ICGA-guided laser photocoagulation. Conclusions: ICGA may be useful to detect leaking spots responsible for DME, enabling less invasive focal laser photocoagulation even in some of the eyes with diffuse DME. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]