In a Phase I-II study, half-body radiotherapy was used to treat 14 dogs with multicentric lymphoma. Using this technique, a radiation dose of 7 Gray (Gy) was delivered to one half of the body in a single exposure. The other half of the body was treated approximately 28 days later. Of 14 treated dogs, 11 (79%) had a measurable decrease in tumor size. Five dogs achieved a complete or partial remission with a mean duration of 102 and 54 days, respectively. In predicting response to therapy, poor prognostic factors included large tumor burdens, advanced disease stage, and chemotherapy-resistant tumors. Side effects of treatment were divided chronologically into acute (radiation sickness, tumor lysis), subacute (bone marrow suppression), and chronic (radiation pneumonitis, lymphoma-cell leukemia) syndromes. Complications were more severe in tumor-bearing dogs when compared with healthy control animals. Dogs with small tumor burdens and minimal internal disease had fewer complications compared with those with more advanced disease.