The study hypothesis is that higher doses of metronomic (low‐dose) chlorambucil will improve outcome without significantly worsening adverse events (AE). Retrospectively, 88 dogs were screened to assess for tolerability and response to chlorambucil utilizing retrospective and prospective data sets, comparing metronomic oral daily doses 4, 6 and 8 mg m2. There were 78 and 70 dogs in the tolerability and efficacy portions, respectively. The severity of gastrointestinal (GI) AE was significantly worse, and time to development of GI events was significantly shorter at 6 mg m2 than at 4 mg m2 (both P < 0.001). Chlorambucil was discontinued earlier in the dogs treated at the 6 mg m2 doses than in the dogs treated at 4 mg m2 (P = 0.015). Thrombocytopenia occurred significantly earlier at 8 mg m2 than at 4 mg m2 (P = 0.017). Higher doses of metronomic (low‐dose) chlorambucil did not provide improved responses and were associated with more AE.