<p>SOCS4 and SOCS5 are members of the suppressor of cytokine signaling (SOCS) protein family, whose biological functions in cancer are critical yet incompletely understood. Oral squamous cell carcinoma (OSCC) patients are at high risk of locoregional recurrence, with 5-year survival rate approximately 50%. Oral carcinogenesis has been associated with tobacco chewing, smoking, and oral premalignant disorders (OPMDs). There is a great need to identify high-risk OPMDs to initiate early oral cancer management. Overactivation of epidermal growth factor receptor (EGFR) signaling leads to significant molecular changes in oral cancer. EGFR expression is regulated by its negative feedback inhibitors SOCS4 and SOCS5. This study aimed to determine the expression of negative EGFR regulators namely, SOCS4 and SOCS5, in OSCC patients with respect to OPMD. The protein and mRNA levels of SOCS4 and SOCS5 were assessed by immunohistochemistry and qRT-PCR in OSCC patients, OPMD patients, Oral Submucous Fibrosis (OSMF) patients and healthy controls. Protein levels of SOCS 4 were significantly overexpressed in (42/50) oral dysplasia and (95/100) oral cancer cases in comparison to normal tissues (8/25). Similarly, SOCS 5 was upregulated in 84% oral dysplasia and 92% oral cancer cases. These findings corroborated with high mRNA levels of SOCS in OSCC and oral dysplasia compared to normal tissues. However, no significant difference in levels of SOCS were observed between oral dysplasia and OSCC patients. OSCC patients with SOCS4 and SOCS5 overexpression had significantly better overall survival. These findings indicate SOCS4 and SOCS5 overexpression as indicator of good prognosis in oral carcinoma patients.</p>