Background: Chemotherapy for multicentric canine lymphoma has favorable results. The gastrointestinal (GI) tract is the most common extranodal site of canine lymphoma, but there have been no prospective studies to determine outcome when dogs with GI lymphoma are treated with chemotherapy.Hypothesis: Treatment with a multiagent chemotherapy protocol is associated with a poor outcome in dogs with GI lymphoma. Animals: Eighteen dogs with histologically confirmed GI lymphoma. Methods: Prospective clinical trial in which dogs with GI lymphoma were treated with a 20-week combination chemotherapy protocol consisting of induction and consolidation phases.Results: Thirteen dogs had primary GI lymphoma and 5 had multicentric lymphoma with GI involvement. The majority of the lymphomas (63%) were of T-cell origin. Overall remission rate was 56%; 9 dogs achieved a complete remission for a median of 86 days (range, 22-420 days) and 1 dog achieved a partial remission for 26 days. Overall median survival time was 77 days (range, 6-700 days). Dogs that failed to achieve a remission (10 versus 117 days; P 5 .002) or had diarrhea at initial presentation (70 versus 700 days; P o .001) had shorter survival times.Conclusion and Clinical Importance: The response and survival of dogs with GI lymphoma treated with multiagent chemotherapy is poor but long-term survival is possible.