The presence of inflammatory reaction in peri-tumoural connective tissue is generally considered as a defense mechanism against cancer, but inflammation tissue in malignant transformation and early steps of oncogenesis has been recently proven to play a supporting and aggravating role in some carcinomas. Aims of this retrospective study were to evaluate in OSCCs the independent association of peri-tumoral inflammatory infiltrate (PTI) with local recurrence (LR) or survival outcome, and to verify whether PTI can be considered a marker of prognosis. Data from 211 cases of OSCC, only surgically treated between 1990 and 2000, were collected and retrospectively analyzed for PTI and the event LR (5 yrs follow-up at least) by means of univariate-multivariate and neural networks analyses. Patients (mean age 65.3 ± 12.4 yrs, M/F = 2.98) showed presence of PTI in 68.2% (144/211): (+) in 27.0%, (++) in 25.6%, (+++) 15.6%; PTI was found reduced in 24.7% of cases and absent in 7.1%. In overall PTI+ve group (n=144), 66 were TNM Stage I, 33 Stage II, 45 Stage III, none Stage IV. LR (mean 6 ± 4 months) was present in 87/211 (41.2%) patients, of which 43/144 (29.8%) in OSCCs with PTI [23 (+), 13 (++) and 7 (+++)] vs. 44/67 (65.7%) in OSCC with PTI -/+ or PTI-ve ones. By univariate analysis, PTI+ve cases showed a significant lower risk to have LR (p <0.0001; OR= 0.2297; CI= 0.1277:0.4134) vs PTI -/+ or -ve ones, especially among cases with higher PTI value (+++) (OR= 0.1718; CI= 0.0749:0.3939). Multivariate analyses (Logit model and neural networks) confirmed the same datum: presence of PTI was an independent predictive variable accounting for a better tumoural outcome without LR (Logit and neural networks values: OR' 0.226; CI= 0.113:0.454; ROC Area = 0.66, respectively). In terms of prognostic significance, elevated PTI was found to have an independent association with the poorest overall survival rate (P = 0.056). Our findings strongly suggest the importance to investigate routinely PTI in OSCCs, as useful marker of tumoral behavior and prognosis, and warrant further studies.