This is what we believe to be the first report of the sign of Leser-Trélat in association with occult adenocarcinoma of the lung. The sign of Leser-Trélat is proposed as a sign of possible occult malignancy, despite various suggestions to the contrary. Also, it is suggested that a tumor-produced humoral factor (eg, transforming growth factor-⍺ [TGF-⍺]) could be responsible for both the acute eruption of the monomorphous seborrheic keratoses and the nearly concomitant development of acanthosis nigricans, which occurred in our case. The possible distinction between a hyperplastic and a neoplastic origin of various types of seborrheic keratosis is discussed in relation to this hypothetical humoral factor. In addition, we suggest a refinement of the definition of the sign of Leser-Trélat and discuss the use of “sign of Leser-Trélat” and “syndrome of Leser-Trélat” in relation to physical findings. All patients with the sign of Leser-Trélat should undergo a thorough evaluation for occult malignancy. (J Am Acad Dermatol 2000;43:386-90.)