Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are rare but devastating diseases, for which no effective specific therapy is currently available. Most patients harbor the D816V mutant of KIT (KIT(D816V)), a constitutively active tyrosine kinase that is essential for pathogenesis, raising hopes that specific inhibition of KIT(D816V) may be therapeutically efficacious. To facilitate testing of new inhibitors in an animal model with similarity to human ASM/MCL, we developed a murine model that is based on retro-orbital injection of P815 cells, a murine mastocytoma line expressing the homologous D814Y mutant of KIT, into syngeneic DBA/2 mice. We found that the systemic disease induced by this approach is highly reproducible and resembles human ASM/MCL. Malignant mast cells were consistently detected in the peripheral blood by morphology and fluorescence-activated cell sorting after a stable latency whose length could be modulated by inoculum size. This easy and inexpensive tumor model should be useful for testing potential drugs with activity against KIT(D816V).