Objective: To assess safety, tolerability, pharmacokinetics, and pharmacodynamics of JNJ-38893777, a potent and selective transient receptor potential vanilloid 1 channel antagonist, following ascending single oral administration in healthy men. Methods: In this single-center, double-blind, placebo-controlled, sequential group, single-ascending-dose phase 1 study, 80 healthy men (18 to 45 years old; body mass index: 18.5 to <30 kg/m2) were randomized to receive either JNJ-38893777 (n=6) or placebo (n=2) per group (total 10 groups) in a doseescalation manner. In part 1, an early tablet formulation was administered under fasting conditions at 5, 15, 45, 125, 250, or 500 mg. In part 2, a new tablet formulation was administered at 250 mg (fasted), 250 (fed, high-fat), 375 (fed, high-fat), or 500 mg (fed, high-fat). Serial blood and urine samples were collected over 120 hours post-dose. Results: JNJ-38893777 concentrations peaked from 3.0 to 5.5 hours (median) after oral administration, and then declined multi-exponentially with a prolonged terminal phase. Renal clearance of JNJ-3889377 was negligible. The Cmax and AUC? of the early formulation increased with increasing doses but less than dose-proportionally over 5-500 mg (fasted) doses. No improvement in exposure was observed with the new tablet formulation (250 mg) under fasting condition. However, high-fat meal substantially increased exposure of JNJ-38893777 by 11- to 22-fold and reduced inter-individual variability from 73-85% to 23-24%. Adverse events were predominately mild to moderate in severity with no evidence of exposure dependence up to 500 mg (fed). No meaningful concentration-related increases in body temperature or QTcF were observed. A significant increase (P<0.05) in heat pain detection threshold (~3ºC) was observed at 250-500 mg (fed). Conclusion: JNJ-38893777 was tolerated at single doses up to 500 mg (fed) and is suitable for further clinical development.