We present a case of hand-foot syndrome (HFS) induced by bolus 5-fluorouracil (5-FU) therapy. A 54-year-old man received bolus 5-FU for adjuvant treatment of rectal cancer. After second cycle, he presented to the clinic with a rash on the both palms accompanied by symptoms of pain, erythema, swelling, and desquamation consistent with grade 2 HFS. HFS appears more frequently with 5-FU delivered by continuous infusion or with the 5-FU oral derivative capecitabine than with bolus 5-FU therapy. HFS is a leading cause of treatment interruption which may impact on the efficacy of the treatment regimen. This possibility must be considered when patient is receiving a bolus 5-FU treatment, and effective and appropriate patient education is an essential part of management to prevent progression to a more severe grade of toxicity by early detection of HFS.