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Background: Serum mRNA is promising prognostic tool for non-invasive malignant disease prognosis of disease, and to study serum mRNA may have important role in the prognosis of disease. Methods: Materials and Methods: Histopathologically confirmed 100 NSCLC cases and 100 healthy control subjects were included in study to evaluate the possible prognostic role of serum EGFR1 and 2 mRNA expressions in lung adenocarcinoma patients. Results: Quantification analysis showed 13.54 and 13.92 mean fold increase in serum EGFR1 &2 expression among NSCLC patients than healthy controls. Patients with larger tumor size had higher EGFR1 & 2 expression which was found to be significantly associated with tumor size (p ¼ 0.02, 0.01). NSCLC patients who had distant metastases (M1) in organs like brain, adrenal, bone etc showed increased EGFR1 & 2 mRNA expression compared to patients without distant metastases (M0) showed significant difference in expression(p < 0.0001).With increasing TNM stage of NSCLC, increased serum EGFR1 & 2 mRNA expression was observed (p < 0.0001). It was found out that a significantly poor overall survival was associated with > 13 fold increase in EGFR1 mRNA expression (p < 0.0001). It was found that a significantly poor progression free survival was associated with patients with > 13 fold increase in EGFR1 mRNA expression (p ¼ 0.001). It was found out that a significantly poor overall median survival was associated with patients with > 13 fold increase in EGFR2 expression (p ¼ 0.02). It was found out that a significantly poor progression free survival was associated with patients with > 13 fold increase in EGFR2 expression (p ¼ 0.001). ROC curves for EGFR1 & 2 were plotted between early and advanced stage NSCLC patients (AUC¼0.95, p < 0.0001, AUC¼0.81 p < 0.0001), presence/absence of distant metastases (AUC¼0.81, p < 0.0001, AUC¼0.73, p < 0.0001) and pleural effusion (AUC¼0.81, p0.009, AUC¼ 0.67, p ¼ 0.03) respectively. Conclusions: Increased circulating mRNAs expression in serum of EGFR1 and 2 genes was found to be associated with worse overall and progression free survival of NSCLC patients. ROC curve analysis showed circulating EGFR1 and EGFR2 mRNA expression in serum could be useful as important predictive indicators for prognosis of NSCLC patients.Legal entity responsible for the study: Mirza Masroor Ali Beg. Funding: Has not received any funding. Disclosure: The author has declared no conflicts of interest.