Background The activation of triggering receptor expressed on myeloid cells-1 (TREM-1) in the presence of microbial components amplifies the inflammatory response. The aim of the present study was to investigate the effect of the modulation of the TREM-1 pathway during empyema in rats.Methods Adult male Wistar rats were subjected to empyema induced by intrapleural injection of Pseudomonas aeruginosa and Staphylococcus aureus. The animals were treated with LP17 (a synthetic TREM-1 inhibitor), a control peptide, or a vehicle (normal saline). Differential cell count, flow cytometry and histological examination were performed to evaluate local inflammatory alterations. Concentrations of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in both pleural effusion and serum were measured by enzyme-linked immunosorbent assay.Results Although differential counts of each type of leukocytes in pleural effusion were not affected by LP17, a marked reduction in neutrophil numbers was seen in LP17 treated rats due to the reduction of both pleural effusion volume and total cell numbers. LP17 administration impaired concentration elevation in tumor necrosis factor-α, interleukin-lβ, and interleukin-6 in both pleural effusion and serum. it was found that survival rate in LP17 treated rats was much higher than that in control rats.Conclusion The modulation of the TREM-1 pathway by the use of LP17 appears to be beneficial during empyema in rats in attenuating pleural and systemic inflammatory responses.