Aim: To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the highly selective oral p38α/β MAP-kinase inhibitor Org 48775-0, a first-in-human study was conducted. Methods: In the SAD study part, an oral dose of Org 48775-0 ranging from 0.3 mg to 600 mg was evaluated in healthy males. In the MAD study part, dose levels of 30, 70 and 150 mg were evaluated with dosing for six consecutive days, twice daily. Both studies were performed in a double-blind, randomized, placebo-controlled, cross-over fashion and evaluated pharmacokinetics (PK), pharmacodynamics (PD; inhibition of LPS-induced TNFα release) and routine clinical and laboratory data. Moreover, the effect of a standardized fat meal on PK and PD parameters of Org 48775-0 was evaluated, and PK and PD parameters of Org 48775-0 were compared between healthy males and postmenopausal females. Results: All adverse events observed in the SAD and MAD cohorts were mild, transient and completely reversible without medical intervention. Pharmacokinetics were linear up to single dose s of 400 mg. Org 48775-0 doses equal to and greater than 30 mg significantly inhibited LPS-induced TNFα release (42.3% increase in inhibition, 95% CI=-65.2; -4.3) compared to placebo. In the MAD study, Org 48775-0 treatment inhibited the LPS-induced TNFα release during the entire steady state period. Levels of inhibition amounted 30-75% for 30 mg, 53-80% for 70 mg, and 77-92% for 150 mg Org 48775-0. Conclusion: This study demonstrates that Org 48775-0 has the capacity to significantly inhibit MAP-kinase activity in humans, without raising safety concerns.