BACKGROUND Oral squamous cell carcinoma (OSCC) is a lethal and deforming disease of rising incidence. With poor 5-year survival rates associated with higher stage disease, there is a need in clinical practice for reliable prognostic determinants to consolidate treatment planning and coordinate therapeutic approaches to improve long-term clinical outcomes for patients. METHODS A retrospective clinicopathological review of 467 OSCC patients with documented clinical outcome and treated in Hong Kong over a 19-year period was undertaken to investigate the potential prognostic role of 4 specific histopathological features of invasive tumour behaviour: perineural invasion (PNI), bone invasion (BNI), lymphovascular invasion (LVI) and extra-nodal extension (ENE) in metastatic neck disease. RESULTS Histopathological data for PNI, BNI, LVI and ENE, and stratified as zero, one, two, three or four positives, were available for 279 patients. A trend for decreased disease-free status was seen with increasing numbers of positive histopathological features, although this was not statistically significant (P = .1076). The time to onset of further disease (loco-regional recurrence and/or distant metastasis) was statistically significant, however, with progressive disease presenting most rapidly with increasing numbers of positive invasive parameters (P = .000152). CONCLUSIONS PNI, BNI, LVI and ENE, especially when found in combination, show promise as prognostic markers of poor clinical outcome following OSCC treatment. Further, multi-centre prospective studies are required to confirm the predictive value of multi-positive histopathological features in clinical practice and to help improve individualised treatment planning.