Background: Although acetaminophen is one of the oldest and most widely used of all analgesic drugs, the incremental benefit of the 1000-mg dose compared with the 650-mg dose has been questioned.Objective: The aim of this study was to assess the relative efficacy of acetaminophen 1000 mg versus acetaminophen 650 mg over a 6-hour period in patients experiencing at least moderate postsurgical dental pain.Methods: This single-center, randomized, double-blind, placebo-controlled, single-dose study enrolled patients aged 16 to 50 years who experienced at least moderate pain after surgical removal of impacted third molars. Each patient received either acetaminophen 1000 mg (n = 239), acetaminophen 650 mg (n = 241), or placebo (n = 60) when they had at least moderate pain and a score on the 100-mm Visual Analog Scale (VAS) postsurgically. Pain intensity and pain relief were measured over 6 hours (VAS 0-100 mm).Results: All 540 patients (52% female; age range, 16-30 years; 95% white) were included in the efficacy analysis. For the primary efficacy endpoint (weighted sum of the pain intensity difference from baseline [PID] and pain relief [PAR] scores over 6 hours [SPRID6]), acetaminophen 1000 mg demonstrated a 24% improvement compared with acetaminophen 650 mg (529.4 vs 427.3; P = 0.001). In addition, acetaminophen 650 mg was significantly superior compared with placebo (P < 0.001). The weighted sum of PID over 6 hours (SPID6), the weighted total pain relief over 6 hours (TOTPAR6), and the percentage of patients with >50% of the maximum possible TOTPAR6 score were significantly greater for patients treated with acetaminophen 1000 mg compared with those receiving acetaminophen 650 mg (P <= 0.006) or placebo (P < 0.001) and for patients treated with acetaminophen 650 mg compared with placebo (P < 0.001). Time to rescue, rescue rates through 4 and 6 hours, and patient global assessment demonstrated similar findings. Patients treated with acetaminophen 1000 mg or 650 mg had a significantly different distribution in times to confirmed perceptible and meaningful pain relief compared with those receiving placebo (P < 0.001). Adverse events were reported by 18.5% of patients, with no clinically important difference between active treatment groups and placebo.Conclusions: Acetaminophen 1000 mg provided clinically meaningful and statistically significantly greater efficacy in treating postsurgical dental pain compared with acetaminophen 650 mg and placebo. The outcomes of this study are limited to the single-dose design of this study. ClinicalTrials.gov identifier: NCT01115673. (Clin Ther. 2012;34:2247-2258) (c) 2012 Elsevier HS Journals, Inc. All rights reserved.