To investigate the effect of pretreatment oral and topical diclofenac on pain reduction during panretinal laser photocoagulation (PRP) for proliferative diabetic retinopathy (PDR). Prospective, randomized, double-masked, placebo-controlled clinical trial. A total of 90 patients with PDR requiring PRP for the first time were assigned randomly to 1 of 3 study groups: oral diclofenac (n = 30), topical diclofenac (n = 31), or placebo (n = 29). Study medications were administrated before the first PRP treatment, and pain levels experienced during and 15 minutes after PRP were recorded on a visual analog scale (VAS). Pain levels during a second PRP session, performed on a later date with no pretreatment medications, also were recorded on a VAS. The primary outcome measures were the mean VAS pain scores during the first PRP treatment. Secondary outcome measures were the mean VAS pain scores 15 minutes after the first PRP and during the second PRP, and reported side effects after the first PRP. Mean VAS pain scores during the first PRP were: oral diclofenac, 25.7+/-19.9; topical diclofenac, 33.8+/-27.9; and placebo, 41.3+/-31.0. The pain score difference between oral diclofenac and placebo was both clinically significant (>or=13) and statistically significant (P = 0.02), whereas differences between oral and topical diclofenac (P = 0.20) and topical diclofenac and placebo (P = 0.33) were not. Multivariate regression analysis for age, gender, and total laser energy demonstrated lower pain levels for both oral diclofenac (P = 0.015) and topical diclofenac (P<0.0001) versus placebo, but no difference between oral and topical diclofenac (P = 0.67). For the first PRP, all 3 groups had lower mean pain scores at 15 minutes after treatment compared with during treatment (P<or=0.0003). Mean pain scores were higher during the second compared with the first PRP for the oral diclofenac (P = 0.02) and placebo (P = 0.05) groups. No significant rate difference for any side effect was found between groups. When given in a single dose, oral diclofenac is an effective pretreatment analgesic agent for reducing the pain experienced during PRP for PDR. The author(s) have no proprietary or commercial interest in any materials discussed in this article.