The Flat-coated Retriever (FCR) is a breed at-risk for histiocytic sarcoma (HS). A haemophagocytic form of HS (HPHS) occurs in the spleen ± other sites such as bone marrow, and is a CD11d+ disease of macrophage origin. Patients with HPHS typically present with regenerative anaemia. Lomustine is a well-accepted, first-line chemotherapy for dogs with HS, but its specific utility in dogs with HPHS has not been previously reported. A cohort of 10 dogs presumptively diagnosed with HPHS via splenic ± bone marrow or liver aspiration cytology were treated with lomustine, plus supportive medications as required. Cytology of liver and bone marrow was diagnostically useful in patients where splenic cytology was less convincing. No dogs experienced significant constitutional or gastrointestinal adverse effects following lomustine administration, though most dogs displayed clinical signs associated with the underlying disease. No patients appeared to derive discernible clinical benefit from chemotherapy. Neutropenia was a common adverse effect of lomustine. Concurrent medications included corticosteroids in all cases, prior to the diagnosis of HPHS, for a provisional diagnosis of immune-mediated haemolytic anaemia. Median survival time of the treated dogs was 24 days from diagnosis (range, 4-67 days). HPHS affecting FCRs appears to have a uniformly poor outcome and is rapidly fatal. Lomustine chemotherapy was unsuccessful in significantly improving outcome in this cohort of patients. Further study of this rare and devastating disease is needed.