The histamine H₄ receptor (H₄R), recently cloned and identified, is a G-protein coupled histamine receptor family expressed in immune cells which plays an important role in inflammation. Recent data evidentiated that H₄R antagonists can decrease airway inflammation and hyperreactivity in animal models of asthma. In the present study we evaluated the effect of the selective H₄R antagonist JNJ7777120 (JNJ) in carrageenan-induced pleurisy, an in vivo model of inflammation, well characterized for cellular and molecular mechanisms. Intra-pleural administration of λ-carrageenan (1% w/v in 0.2 ml sterile saline) determined an intense recruitment of leucocytes in pleural exudates and in lung tissues, activated inducible nitric oxide (NO) synthase and cyclooxygenase-2, thus increasing the generation of harmful autacoids such as NO and pro-inflammatory prostaglandins, PgE₂ and 6-ketoPgF(1α), increased cellular and DNA oxidative stress, measured as malondialdehyde and 8-OH-deoxyguanosine and the local generation of IL-1β and TNF-α. Moreover, the activity of caspase-3, an early marker of apoptosis was also activated by λ-carrageenan injection. The pre-treatment with JNJ (5-10 mg Kg⁻¹ b.wt., given intrapleurally), 60 min before carrageenan markedly reduced all the studied parameters. This study clearly demonstrated that histamine H₄R antagonists have anti-inflammatory effects and could have potential therapeutic application for the treatment of inflammatory diseases.