Background: Drug combinations with complementary mechanisms of action are able to achieve effective analgesia at lower doses, thereby reducing the risk of adverse effects (AEs). This study evaluated the analgesic efficacy and tolerability of two fixed-dose combinations (FDCs) of ibuprofen/tramadol (IBU/TRA) compared with tramadol and a placebo. Methods: This multicenter, randomized, double-blind, dose-finding, pilot clinical trial compared IBU/TRA (400/37.5 mg and 400/75 mg) with 100 mg of tramadol and a placebo in patients with moderate-to-severe pain following dental surgery. The primary endpoints were pain intensity at 6 h (PI6h) and the pain intensity difference from baseline to 6 h (PID6h). PID7h, the sum of pain intensity differences from baseline to 7 h (SPID0-7h), pain relief (PAR(7h)), total pain relief (TOTPAR(7h)), the use of rescue medication and AEs were also assessed. Results: Seventy-two patients were randomized and evaluated. Both FDCs showed superiority over the placebo for PI6h and PID6h (p < 0.05) but were not significantly different from 100 mg of tramadol. The statistical superiority of FDCs over the placebo was observed for PID7h, SPID0-7h, PAR(7h) and TOTPAR(7h). The percentage of patients receiving rescue medication was higher in the placebo (94.1%) and tramadol (52.6%) groups than the FDC groups (35.3% and 36.8% for 400/37.5 mg and 400/75 mg, respectively). A post hoc analysis showed that the FDCs had a superior analgesic efficacy to 100 mg of tramadol in the SPID0-4h (p < 0.005). The incidence of AEs was comparable between treatment groups. Conclusions: Both FDCs of IBU/TRA provided superior analgesic efficacy compared to the placebo. We propose using SPID0-4h as the preferred variable for evaluating the efficacy of this type of drug combination.