Objective: This study was aimed to assess the efficacy of Tc-99m-3PRGD2 imaging for evaluating both early treatment response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and prognosis in advanced-stage lung adenocarcinoma. Material and Methods: Eighteen patients with lung adenocarcinoma were enrolled for EGFR-TKIs therapy. Tc-99m-3PRGD2 SPECT/CT and planar imaging were performed pre- and post-therapy. The tumor to nontumor (T/NT) ratio and percentage change in T/NT ratio were assessed for the treatment response. Receiver operator characteristic (ROC) analysis was utilized to analyze the power of identifying responders based on the changes in T/NT ratios. Results: After treatment, 10 patients had partial response (PR), and 6 patients stable disease (SD), while 2 patients progressive disease (PD). The mean changes in T/NT ratios on SPECT/CT and planar images in PR group were 35.8% and 15.0% and in SD group were 8.9% and 0.7%, while in PD group were 76.1% and 18.7%, respectively. For ROC analysis, using a cutoff value of 23.8% decrease in T/NT ratio on SPECT/CT images, the sensitivity and specificity in identifying responders were 80.0% and 87.5%, respectively. The median progression-free survival (PFS) for patients with responders and nonresponders (on Tc-99m-3PRGD2 SPECT/CT) was 18 months (95% CI 5.8-30.2 months) and 7 months (95% CI 5.2-8.8 months), respectively (p = 0.006). Conclusion: Tc-99m-3PRGD2 imaging can evaluate the early response to EGFR-targeted therapy and predict the PFS of lung adenocarcinoma patients.