The presence of multiple seborrheic keratoses appearing abruptly in association with an underlying malignancy is known as Leser-Trélat sign, a rare paraneoplastic cutaneous syndrome. Although this finding is most commonly associated with solid organ tumors, it also can be a clue for the presence of underlying hematologic malignancies. We present a unique case of Leser-Trélat sign in a 20-year-old man who experienced a relapse of pre–B-cell acute lymphocytic leukemia (ALL) that was previously treated with multiple courses of chemotherapy and external radiation therapy. The patient was admitted for a new cycle of chemotherapy with etoposide and cyclophosphamide and was noted to have an eruption of yellowish brown papules and plaques over his upper body. Biopsy of a representative lesion was consistent with seborrheic keratosis. A large number of rapidly appearing seborrheic keratoses is an uncommon finding in young patients and should be considered clinically suspicious as a potential indicator of Leser-Trélat sign. A thorough history and physical examination should be performed in patients presenting with this sign to rule out possible internal solid organ and hematologic malignancies.