The reconstruction of loss of substance due to trauma or oncological excision may have relevant functional and aesthetic implications. We report our experience in twenty-one cases of propeller flaps for the treatment of loss of substance of the upper and lower limbs. The etiology of defect was tumor excision in nine cases, trauma in seven cases, surgical wound complications in four cases, and chronic osteomyelitis in one case. Clinical results were favorable in most cases and eighteen flaps survived. We observed an overall complication rate of 33% with four cases of superficial epidermolysis that spontaneously healed and three cases of partial flap loss ranging from 10 to 50% that required surgical revision by means of skin graft (two cases) or ALT free flap (one case). Propeller flap harvesting requires great care and experience, and potential complications may occur even in expert hands. When indicated by the characteristic of the defect, these flaps can be a useful surgical option for the treatment of loss of substance of upper and lower limbs.