Lung cancer is the leading cause of cancer deaths in the U.S. and a substantial world health problem in general. Standard treatment became chemoradiotherapy (ChT/RT) for inoperable locally advanced Non-Small Cell Lung Cancer (NSCLC). Approximately 85% NSCLC overexpress the EGFR. Our prospective phase II trial investigated EGFR-TKI (erlotinib) as a radiosensitizer for inoperable Stage III NSCLC patients who also received standard ChT/RT. 48 Stage III NSCLC patients were enrolled from 3/2008 through 6/2010. Eligibility included Zubrod performance status (PS) = < 1, weight loss = < 5% over past 3 months, FEV1 > = 1.0 L, adequate hematologic, hepatic, and renal functions. ChT/RT was given every Monday followed by erlotinib/RT on Tuesday-Friday and erlotinib alone over the weekend. RT (63 Gy in 35 fractions) with weekly paclitaxel (45mg/m2) / carboplatin (AUC = 2) and erlotinib (150 mg p.o. daily except on the day of chemotherapy) were given for 7 weeks. After one month break, patients received two cycles consolidation of paclitaxel (AUC = 6) and carboplatin (200mg/m2). EGFR mutation analysis was performed for 41 patients. The Response was measured by RECIST criteria (v3.0) by CT scan after completion of ChT/RT. Fisher's exact and Kaplan-Meier's estimates were used for the statistical analysis. Primary endpoint was to determine efficacy of erlotinib/radiotherapy after ChT/RT measuring time to progression. 46 patients completed the entire treatment are evaluable for response. All had PS KPS > = 80, 17 (37%) were female, 23 adenocarcinoma, and 87% former or current smokers, with median age 63 year-old (range: 46 - 81). Responses showed 14 (30%) CR, 23 (50%) PR and 9 (20%) stable or progressive disease. Five in 41 patients (12%) had EGFR mutation (EGFR-M), all adenocarcinoma with 2 females, compared to none of squamous histology (p = 0.05). CR and non-CR were 3 and 2 in the EGFR-M group compared to 11 and 25 in the EGFR-wild group (p = 0.32), respectively. The median OS and PFS were 16.2 months and 16.9 months, respectively. 1-year and 2-year OS were 84.4% and 72.9% (EGFR-M 80.0% and 80.0%; EGFR wild type: 59.9% and 35.5, p = 0.52) and PFS 55.0% and 31.4% (EGFR-M 20.0% and 20.0%; EGFR wild type: 59.9% and 35.5, p = 0.34), respectively. Toxicity showed 2 grade 3 acne, 1 Grade 3 esophagitis, 3 Grade 3 pneumonitis and no Grade 4 - 5. One year OS was 74.7% in grade 0 - 1 acne group and 92.3% in grade 2 - 3 acne group, respectively. This prospective phase II clinical study demonstrated an excellent 1-year OS 84 % and median OS 25.8 months. All EGFR-M were seen in adenocarcinomas. Erlotinib demonstrated a radiosensitization effect.