Thirty-five dogs with appendicular osteosarcoma were treated with 5 doses of doxorubicin (30 mg/m2 of body surface, i.v., every 2 weeks). Surgical excision of the primary tumor was performed 13 days after the second (n = 18) or third (n = 17) treatment, and the subsequent doxorubicin treatment was given the day following surgery. Resected tumors were evaluated histologically to determine response to preoperative chemotherapy (ie, percentage of the tumor that was necrotic). Survival data for the 35 dogs were compared with survival data for a historical control group, consisting of 162 dogs with appendicular osteosarcoma treated by amputation alone. Administration of doxorubicin at 2 week intervals was well tolerated. Three dogs were alive and did not have evidence of disease at the time of reporting. Of the remaining 32 dogs, 3 died or were euthanatized because of cardiomyopathy presumably caused by doxorubicin; 1 died suddenly 116 weeks after initiation of treatment; and the remaining 28 were euthanatized because of problems documented to be related to distant metastases. Thirteen dogs (40.6%) were euthanatized because of pulmonary metastases, 10 dogs (31.3%) were euthanatized because of bone metastases, and 5 dogs (15.6%) were euthanatized because of metastases in other sites. The proportion of dogs euthanatized because of bone metastases was significantly (P < 0.001) higher for the study group than for the control group. Median survival time for the 35 dogs that received doxorubicin was estimated to be 52.3 weeks, and 1- and 2-year survival rates were estimated to be 50.5 and 9.7%, respectively. Survival time was significantly (P < 0.0001) longer for these dogs than for control dogs.(ABSTRACT TRUNCATED AT 250 WORDS)