Laetiporus sp. is recognized as a fungal species traditionally used for medicinal purposes. This study investigated the in-vitro effects of solid-state fermented Laetiporussulphureus ethanol extracts (LSE) for their immunomodulatory potential. Bioactive levels detected in the LSE on different days throughout the fermentation period revealed that the 12 th day was the most efficient, with 7.19 ± 0.66 GAE/g DM crude phenolic content, 2.71 ± 0.03 UAE/g DM crude triterpenoid content, 12.93 ± 0.88 GCE/g DM crude polysaccharides, and 96.44 ± 0.2 mg/g DM ergosterol content. In-vitroLSE tests on chPBMC showed no cytotoxicity within a range of 0.05-1 mg/mL, but LPS-inhibited cell viability was improved, as well as LPS-induced nitric oxide (NO) production and mRNA levels of nuclear factor kappa B (NFkB), Tolllike receptor 4 (TLR4), inducible nitric oxide synthase (iNOS), and interleukin (IL)-1bwere attenuated Furthermore, the direct application of LSE on chPBMC showed a small but not significant increase in NFkB, TLR4, and iNOS mRNA expression compared with the control group. These results indicate the potential of LSE to modulate LPStriggered inflammation processes involving TLR4 and NFkB mediation. However, further experiments are required to determine the specific pathway.