Abstract Expression of cancer-associated biomarkers represents a great potential for a more precise diagnosis for patient stratification and more personalized treatment of oral squamous cell carcinoma (OSCC). The aim of this study was to develop an immunohistochemistry-based malignancy index diagnostic system (IHC-MIDS) based on the expression of a panel of several molecules expressed by different tumor components and involved in different oncogenic pathways. IHC was performed on paraffin embedded formalin fixed tissue samples from 102 patients for the following biomarkers: p16, p53, ki67, p75NTR, LoxL4, aSMA, Foxp3, CD68, CD 163, CD80, FVIII and D2-40. The stained tissues were scanned and quantified using Immage J open source software. An IHC-MIDS score was developed using correlation-based feature selection algorithm. IHC-MIDS was able to stratify OSCC lesions for several clinical pathological features, including the risk of recurrence. This study shows that a scoring system based on expression of a panel of biomarkers is more precise than the use of a single biomarker and that it can be used for risk stratification of OSCC lesions in order to guide further management. Citation Format: Martha Rolland Jacobsen, Harsh Dongre, Israa Ahmed, Vidisha Tuljaurkar, Prathamesh S. Pai, Asawari Patil, Dipak Sapkota, Anne Christine Johannessen, Nenad Filipovic, Milind Vaidya, Sharda Sawant, Daniela Elena Costea. Development of a molecular diagnostic tool for more precise diagnosis of oral squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 45.