Compartment syndrome is a documented and potentially lethal complication of thrombolytic therapy. With the increasing use of catheter-directed thrombolytic therapy, a high index of suspicion for the potential occurrence of this surgical emergency must be maintained. Errors of omission in the diagnosis of compartment syndrome, even for a few hours, may lead rapidly to limb loss, renal failure, and possibly death. The authors present a case of compartment syndrome arising in the forearm of a patient being treated with continuous catheter-directed thrombolytic therapy for an occluded arterial bypass graft associated with an ischemic lower extremity. Specific to this presentation is their management of compartment syndrome during thrombolytic therapy as well as previously unreported use of a homograft (cadaveric skin) to control ongoing blood loss from a fasciotomy site in this fully anticoagulated patient. The authors think their management in this case may help to provide direction to others faced with a similar, increasingly common, surgical dilemma.