PURPOSE:For nonoperable stage I non-small cell lung cancer, stereotactic body radiation therapy (SBRT) has emerged as a standard treatment option. We aimed to compare the clinical outcomes of lung SBRT between patients with versus without pathologic cancer diagnosis. METHODS AND MATERIALS:We included patients treated by SBRT for a single pulmonary lesion between July 2009 and July 2017. Patients in the clinical diagnosis group had a positron emission tomography/computed tomography scan showing hypermetabolism, growth of the mass on sequential computed tomography, and were not eligible for biopsy, refused biopsy, or had an inconclusive biopsy. For each of those patients, a matched pair in the pathologic diagnosis group was identified by matching for patient, treatment, and tumoral characteristics. We performed a power calculation to estimate the sample size required to detect a difference arising from a 5% or 15% rate of benign processes in the group without pathology. RESULTS:A total of 924 lung SBRT treatments were performed among 878 patients from 2009 to 2017. Within this population, 131 patients were treated based on clinical findings. They were matched with 131 patients with a pathologic diagnosis who received treatment. At 3 years, no significant differences were observed in overall survival (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.7-2.1), local control (HR, 0.9; 95% CI, 0.4-2), or regional (HR, 0.5; 95% CI, 0.2-1.4) or distant recurrence (HR, 0.6; 95% CI, 0.3-1.1). CONCLUSIONS:In our population, we found no clinically significant difference in patterns of recurrence or survival after lung SBRT for patients who had received clinical versus pathological diagnoses. There was, however, a trend toward more distant recurrences in the pathologic diagnosis group. Our power calculation suggests that data from multiple institutions would be required to rule out a difference in outcomes due to 5% to 15% of clinically diagnosed cases being treated for benign processes.