Hand-foot syndrome (HFS) is a well-known adverse event associated with capecitabine, a prodrug of 5-Fluorouracil (5-FU). HFS manifests as acral erythema, with swelling and dysesthesia of the palms and plantar aspects of the feet, which in the absence of dosage reduction or drug cessation, progresses to moist desquamation and ulceration, resulting in serious infections and loss of function. We report a case of HFS, with scleroderma-like changes, apparently induced by capecitabine. In our case, capecitabine, given in the recommended dosage was observed to lead to hyperpigmentation of the palms and soles, followed by a distinct keratoderma-like thickening unfamiliar to usual cases of HFS. This case may provide important clues for revising the definition of HFS, and allow the formation of effective preventive strategies for this side effect of chemotherapy.