The COVID-19 outbreak is affecting people worldwide. Many infected patients have respiratory involvement that may progress to acute respiratory distress syndrome. This pilot study aimed to evaluate the clinical efficacy of low-dose whole-lung radiation therapy in patients with COVID-19 pneumonia. In this clinical trial, conducted in Iran, we enrolled patients with COVID-19 who were older than 60 years and hospitalized to receive supplementary oxygen for their documented pneumonia. Participants were treated with whole-lung irradiation in a single fraction of 0.5 Gy plus the national protocol for the management of COVID-19. Vital signs (including blood oxygenation and body temperature) and laboratory findings (interleukin-6 and C-reactive peptide) were recorded before and after irradiation. Between May 21, 2020 and June 24, 2020, 5 patients received whole-lung irradiation. They were followed for 5 to 7 days to evaluate the response to treatment and toxicities. The clinical and paraclinical findings of 4 of the 5 patients (patient 4 worsened and died on day 3) improved on the first day of irradiation. Patient 3 opted out of the trial on the third day after irradiation. The mean time to discharge was 6 days for the other 3 patients. No acute radiation-induced toxicity was recorded. With a response rate of 80%, whole-lung irradiation in a single fraction of 0.5 Gy had encouraging results in oxygen-dependent patients with COVID-19 pneumonia.