BACKGROUND Severe musculoskeletal trauma can trigger an inflammatory response, and an excessive inflammatory response can lead to systemic inflammatory response syndrome and multiorgan failure. High-mobility group box 1 (HMGB1) is an early mediator pro-inflammatory cytokine in sterile injuries and a late cytokine mediator in infection and sepsis. Previous research has shown that administration of systemic lidocaine can inhibit HMGB1 expression in macrophages of septic rats. The aim of this study was to demonstrate the efficacy of systemic lidocaine to inhibit HMGB1 mRNA and protein in a BALB/c mouse model of sterile inflammation due to closed fracture musculoskeletal injury. METHODS Twenty adult male BALB/c mice were divided into lidocaine and control groups. The closed fracture musculoskeletal injury was performed by breaking the left thigh bone of the mice. Four hours after undergoing the closed fracture, the lidocaine group was treated with lidocaine intravenous (2 mg/kg). The same volume of distilled water was injected into the control group instead of lidocaine. HMGB1 mRNA expression was examined with real-time polymerase chain reaction, and HMGB1 protein level was determined with enzyme-linked immunosorbent assay. RESULTS The expression of HMGB1 mRNA and protein levels in mice that sustained inflammation due to a closed fracture musculoskeletal injury was significantly decreased in the lidocaine group (P < 0.00 and P < 0.00 for mRNA and protein, respectively). CONCLUSIONS Intravenous administration of lidocaine effectively inhibited the inflammatory process in BALB/c mice that underwent closed fracture musculoskeletal injury by suppressing HMGB1 mRNA transcription and HMGB1 protein translation.