Background: Amplification and overexpression of the EGFR gene and surface protein have been described in up to 80% of pancreatic tumors, making EGFR an attractive target in developing new adjuvant therapy for pancreatic adenocarcinoma (PDAC). Inhibition of EGFR has been suggested to provide additive activity when combined with capecitabine and radiation. Here we evaluate the antitumor activity and toxicity profile of erlotinib combined with adjuvant chemoradiotherapy (CRT) and chemotherapy. Methods: 50 patients with resected stage I/II PDAC were enrolled in a phase II trial of adjuvant erlotinib and capecitabine administered concurrently with IMRT (50.4 Gy), followed by 4 cycles of erlotinib and gemcitabine. Results: Median length of follow-up was 18.2 months (IQR, 13.8-27.1). Seventy-nine percent of tumors were of the pancreatic head, 85% had nodal involvement, and 17% had positive margins. Median RFS was 15.6 months (95% CI, 14.1-17.1), local RFS 21.1 months (95% CI, 17.1-25.1), and OS 24.4 months (95% CI, 17.1-31.6). Local recurrence was only observed in 19% patients and synchronous recurrence in 8%. Patients with maximum tumor diameter of ≤3 cm showed superior RFS (17.9 vs. 14.0 months; P=0.049), as did patients with cutaneous reaction to erlotinib (16.3 vs. 9.3 months, P=0.021). Superior OS was associated with less than median (32.3U/mL) pre-CRT CA19-9 values (28.2 vs. 19.0 months, P=0.012). During CRT, 31% patients experienced grade 3 toxicity and 2% grade 4, while 31% patients required a treatment break/stopped treatment early. During post-CRT chemotherapy, 35% patients experienced grade 3 toxicity and 8% grade 4, while 30% required a dose reduction. Conclusions: Results of this phase II trial suggest erlotinib combined with standard adjuvant CRT and chemotherapy provides excellent local disease control and reasonable tolerability compared with existing adjuvant regimens. Patients with maximum tumor diameter of ≤3 cm, cutaneous reaction to erlotinib, and less than median pre-CRT CA19-9 values appear to especially benefit from this new adjuvant regimen. Clinical trial information: NCT00962520.