Congenital leukemia and leukemoid reactions may be indistinguishable on clinical and histologic grounds and are highly associated with trisomy 21. This report characterizes a specific vesiculopustular skin eruption in an infant with Down syndrome and a congenital leukemoid reaction. On the first day of life an unusual vesiculopustular eruption developed, starting in areas of cutaneous trauma. A biopsy revealed immature myeloid cells in an epidermal spongiotic vesiculopustule and in a perivascular distribution, suggestive of leukemia cutis. As the peripheral blood smear normalized, the eruption cleared. Myelodysplasia subsequently developed and evolved into acute myelogenous leukemia. This is the first detailed report of a specific skin infiltrate caused by the immature cells of a leukemoid reaction. Skin infiltration by immature myeloid cells during a congenital leukemoid reaction may portend an aggressive course of the myeloproliferative disorder.