To evaluate once-daily nepafenac 0.3% to prevent and treat ocular pain and inflammation after cataract surgery. Sixty-five centers in the United States and Europe. Randomized double-masked vehicle- and active-controlled phase 3 study. Patients received nepafenac 0.3% once daily, nepafenac 0.1% 3 times daily, or their respective vehicles from day −1 to day 14 after cataract extraction. An additional drop of study drug was administered 30 to 120 minutes preoperatively. The primary endpoint was the percentage of patients with a cure for inflammation (score of 0 for both aqueous cells and flare) at day 14. Of randomized patients, 817 received nepafenac 0.3%, 819 received nepafenac 0.1%, and 200 and 206 received the respective vehicles. Significantly more nepafenac 0.3% patients had no inflammation (68.4% versus 34.0%) and were pain free (91.0% versus 49.7%) at day 14 than vehicle patients (both P<.0001). Nepafenac 0.3% was noninferior to nepafenac 0.1% for inflammation (95% confidence interval CI, −5.73% to 3.17%) and pain-free rates (95% CI, −3.08% to 2.70%). At all postoperative visits, fewer treatment failures (P≤.0012) and more clinical successes (P≤.0264) were observed with nepafenac 0.3% versus vehicle. Nepafenac 0.3% was well tolerated and had a safety profile comparable to that of nepafenac 0.1%. Once-daily nepafenac 0.3% was noninferior to nepafenac 0.1% 3 times daily for prevention and treatment of ocular inflammation and pain following cataract surgery. The safety of nepafenac 0.3% was comparable to that of nepafenac 0.1%, with the added convenience of once-daily dosing. Drs. Modi, Lehmann, Walters, Fong, Christie, Roel, Nethery, and Reiser have been paid consultants to Alcon Research, Ltd. Ms. Sager is an employee of Alcon Research, Ltd. Drs. Tsorbatzoglou, Philipson, and Traverso have no financial or proprietary interest in any material or method mentioned.