Treatment of feline vaccine-associated sarcoma (VAS) is challenging, in part due to the high likelihood of tumour recurrence despite aggressive local therapy. Lomustine is potentially an attractive agent to add to the current treatment armamentarium. In this de-escalating phase I/II prospective trial, 28 cats with measurable VAS were treated at target dosages of 38–60 mg m−2 every 3 weeks until disease progression. The overall response rate was 25%, with a median progression-free survival and median duration of response of 60.5 and 82.5 days, respectively. Haematologic toxicity, specifically cumulative neutropenia, was significant, and dose reductions and treatment delays were common. Although these data support further investigation of lomustine for the treatment of VAS, safe, multidosing protocols must first be determined.