Objective: Porphyromonas gingivalis lipopolysaccharide (PgLPS) displays significant amount of lipid-A heterogeneity, containing both tetra (LPS1435/1449) and penta-acylated (LPS1690) isoforms. We recently demonstrated PgLPS isoforms differentially modulate the immuno-inflammatory response in human gingival fibroblasts (HGFs). This study aimed to unravel the molecular mechanism by which PgLPS regulates the immuno-inflammatory activity, lipid peroxidation and apoptotic pathways in HGFs. Methods: Primary HGFs were treated with PgLPS1435/1449 and PgLPS1690 in both dose-dependent and time-dependent experiments. Modulation of lipid peroxidation and apoptotic pathways was examined using gene-expression arrays and validated by qPCR and western blot. Antibody blocking assays were performed for TLRs (TLR2/TLR4) and signal transduction pathways (MAPK/NF-kB) to determine the mechanisms of PgLPS-HGFs interactions. Down-stream markers related to immuno-inflammatory response were examined by qPCR, ELISA and western blot. Results: PgLPS1690 up-regulated anti-oxidant molecules like thioredoxin and superoxide dismutase, whereas PgLPS1435/1449 down-regulated the expression of these molecules in a time-dependent manner. In contrast to PgLPS1435/1449, apoptosis pathway molecules such as caspases 3, 5, 8 and 9 were induced by PgLPS1690. PgLPS1690 induced chemokines CCL2, CXCL10 and GM-CSF. Interestingly, PgLPS utilized different mechanisms (TLRs related signal transduction pathways) in modulating host innate response, which could account for aforementioned observations. Conclusions: This study unraveled for the first time the molecular mechanisms of heterogeneous PgLPS isoforms to disguise host immune response for Pg survival and proliferation in gingival tissues. The current findings may contribute to the development of novel strategies for controlling periodontal diseases (Supported by Hong Kong Research Grants Council, GRF No. HKU766909M to LJJ).