The high incidence and mortality of lung carcinoma in Egypt necessitates studying the factors that may be implicated in non-small cell lung carcinoma (NSCLC) pathogenesis and could affect patient management. The aim was to study FHIT, epidermal growth factor receptor (EGFR), and MSH2 protein expression in Egyptian patients with NSCLC. Immunohistochemical staining for FHIT, EGFR, and MSH2 was performed on 64 specimens from NSCLC patients and correlated with prognostic parameters, response to therapy, and overall survival. FHIT loss was observed in 64% of NSCLC patients and was significantly associated with SCC (P=0.003) and poor tumor grade (P=0.043). EGFR overexpression was observed in 47% of NSCLC patients and was significantly associated with SCC (P=0.002). MSH2 was reduced in 23.4% of NSCLC patients and was significantly associated with adenocarcinoma (P=0.024). In a univariate analysis, a significant relationship was seen between the poor overall survival in NSCLC patients and high T-stage (P=0.029), presence of metastasis (P=0.014), advanced-stage grouping (P=0.004), and FHIT loss (P=0.033). Further, FHIT loss was significantly related to disease progression in patients treated with chemotherapy (P=0.038). We conclude that all 3 markers play a role in the development of NSCLC in Egyptian patients. We suggest that FHIT loss be used as a predictor for progression in chemotherapy-treated NSCLC patients.