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PURPOSE To investigate the effects of panretinal photocoagulation (PRP) on macular thickness and macular nerve fiber layer thickness in eyes with proliferative diabetic retinopathy. METHODS Single-center, randomized clinical trial (n = 40 eyes). Proliferative diabetic retinopathy was treated with 1,500 burns given as Pascal 20-millisecond single-session PRP (SS-PRP) or as multiple-session PRP (100 milliseconds, MS-PRP) over a 4-week period. The main outcome measures included optical coherence tomography measurements of total retinal thickness and nerve fiber layer at the macula, visual acuity, and proliferative diabetic retinopathy regression and were recorded at baseline, 4 weeks, and 12 weeks. Optic disk photographs were graded by masked a glaucoma specialist. RESULTS At 12 weeks, in the SS-PRP group, there was no significant change in total nerve fiber layer thickness from baseline (4 weeks; +7.2 μm, P = 0.78; 12 weeks, -1.8 μm, P = 0.95). There was a significant increase in total retinal thickness for the MS-PRP group at 4 weeks from baseline (96 ± 17 μm; P < 0.001) and at 12 weeks (56 ± 21 μm; P = 0.0167). After 4 weeks in the MS-PRP group, total nerve fiber layer thickness increased significantly by 31 ± 54 μm (P = 0.029) from baseline, with a significant reduction at 12 weeks from baseline (35 ± 63 μm; P = 0.034). There was no change among groups for optic nerve appearance postlaser. At 12 weeks, the mean visual acuity was 81 ± 6 letters (SS-PRP group), compared with 77 ± 15 letters in the MS-PRP group (95% confidence interval, 5.2 to 9 letters; P = 0.286). For the SS-PRP group, a positive effect on proliferative diabetic retinopathy regression was observed in 74% of eyes compared with 53% of the eyes in the MS-PRP group (P = 0.31). CONCLUSION Compared with 20-millisecond SS-PRP, eyes treated with conventional 100-millisecond single-spot delivered over multiple sessions showed increased total macular thickness at 4 weeks, with a thinning of macular nerve fiber layer at 12 weeks.