Purpose: Systemic disease can manifest oral signs at an early phase, which may be crucial for the diagnosis and timing of treatment. This report describes two patients who presented with gingival enlargement as an early sign of acute leukemia. Methods: Two patients presented with oral symptoms including severe gingival enlargement. The progress of their symptoms was associated with underlying systemic disease. Results: The patients were transferred to the Department of Hematology and diagnosed with acute myelomonocytic leukemia. They received appropriate treatment and survived. Conclusions: Gingival enlargement can be caused by underlying systemic diseases. Accurate diagnosis and timely referral are important for preventing a fatal situation. It must be emphasized that some oral signs and symptoms may be closely correlated with systemic diseases.