Objective: Titanium can alter peri-implant mucosa cytokine response to microbiological and chemical stresses. This work used organotypic titanium-oral mucosa model to evaluate oxidant resistance and cytokine response to Porphyromonas gingivalis lipopolysaccharide (Pg LPS) and nicotine. Material and Methods: Seeding gingival keratinocytes on collagen gels with fibroblasts and adding titanium grade (Ti-Gr) 4, Ti-Gr 5, or hydroxyapatite discs developed an organotypic titanium-oral mucosa model. Pg LPS (1 l/mL), nicotine (1.54 mM), or both were given to the model. The Luminex® xMAPTM technology measured interleukin (IL)-1β, IL-1Ra, IL-8, monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor levels in culture media. Cultured tissues were paraffin-blocked and immunohistochemistry was used to measure nuclear factor erythroid 2 like 2 (NFE2L2/NRF2), 8-hydroxyguanosine (8-OHdG), and Parkinsonism-associated deglycase (PARK7/DJ-1). Statistical analysis included one-way analysis of varianceand Tukey's HSD. Results: Nicotine and Pg LPS+nicotine increased IL-1β and IL-1Ra secretions in Ti-Gr 4, Ti-Gr 5, and hydroxyapatite groups (p<0.01). Pg LPS alone (p<0.01) and in conjunction with nicotine (p=0.021) enhanced MCP-1 production, but nicotine alone lowered it (p=0.024). IL-8 concentrations rose in all test groups (p<0.01). All groups treated with nicotine, LPS, or both showed increased 8-Hydroxydeoxyguanosine and NFE2L2/NRF2 immunostainings (p<0.01), whereas PARK7/DJ-1 expression remained unchanged. When assessed without inducers, Ti-Gr 4, Ti-Gr 5, or hydroxyapatite groups showed no significant variations in cytokine secretion patterns, NFEL2/NRF2, 8-OHdG, or PARK7/DJ-1 immunostainings (p>0.05). Conclusion: Titanium did not affect cytokines or oxidant resistance molecules in our organotypic model without inducers. However, Pg LPS, nicotine, and their mixtures enhance cytokines and oxidative resistance molecules.