Licofelone, a novel dual anti-inflammatory drug that inhibits 5-lipoxygenase (5-LOX) and cyclooxygenase (COX), has recently been defined to have therapeutic effects in osteoarthritis. Both 5-LOX and COX play functional roles in the pathogenesis of glomerulonephritis in children as well. Interleukin-18 is a pro-inflammatory cytokine. It remains unclear whether licofelone can ameliorate inflammatory response of human mesangial cells (HMC) exposed to interleukin-18. In this study, HMC were cultured and exposed to interleukin-18 with or without pre-treatment of licofelone. COX-2 and 5-LOX enzyme activities in mesangial cells were determined with chromometry or high-performance liquid chromatography. Prostaglandin E2, cysteinyl leukotriene, monocyte chemotactic protein-1 and interferon-γ concentrations in culture medium were measured using an enzyme-linked immunosorbent assay. Western blotting was employed to detect phosphorylated mitogen-activated protein kinases ERK1/2, p38 and JNK1/2 in HMC. It was found that licofelone attenuated interleukin-18-induced COX-2 enzyme activity in HMC and prostaglandin E2 release in a dose-dependent manner. Similarly, licofelone inhibited interleukin-18-induced 5-LOX enzyme activity and leukotriene release. Licofelone reduced interleukin-18-induced phosphorylation of p38 mitogen-activated protein kinase and suppressed monocyte chemotactic protein-1 and interferon-γ synthesis. Moreover, licofelone inhibited IL-18-induced proliferation of mesangial cells. We conclude that licofelone inhibits interleukin-18-induced pro-inflammatory cytokine release and cellular proliferation in HMC, which may represent a really interesting therapeutic approach for glomerulonephritis in children.