PURPOSE: To evaluate the feasibility of adaptive planning using positron emission tomography-computed tomography (PET-CT) in locally advanced non-small cell lung cancer. METHODS AND MATERIALS: Patients with locally advanced non-small cell lung cancer receiving definitive radiation therapy (RT) were eligible. Initial planning PET-CT was performed and a conventional RT plan (2 Gy/fraction to 60 Gy) was designed. A second planning PET-CT was obtained at ~50 Gy. Dose escalation to ~70 Gy for residual fludeoxyglucose-avid disease was pursued at the discretion of the treating oncologists. The primary endpoint was feasibility of adaptive planning using interim PET-CT. Normal tissue dose-volume parameters were calculated for both adaptive and simulated nonadaptive plans. RESULTS: From 2012 to 2014, 33 eligible patients were enrolled and underwent planning PET-CT, 3 of which were found to have new distant metastases. Of 30 patients who initiated RT, interim PET-CT was obtained in 29. This showed complete response in 2 patients, partial response/stable disease in 24, and new distant metastases in 3. Selective dose escalation was performed in 17 patients. For those receiving a boost, the median gross tumor volumes pre-RT and at ~50 Gy were 78 mL and 29 mL, respectively (P = .01). Reasons for no dose escalation were normal tissue constraints (n = 3), poorly defined residual disease (n = 2), acute toxicity (n = 1), and refusal of further therapy (n = 1). Adaptive planning compared with a simulated nonadaptive approach allowed for significant dose reductions to the lungs, heart, and esophagus (all P < .01). CONCLUSIONS: Adaptive planning using PET-CT was feasible and allows for significant dose reductions to normal tissues compared with traditional planning techniques.