BACKGROUND Atherosclerosis and malignancies are leading causes of morbidity and mortality worldwide. In lower-extremity arterial disease (LEAD), progressing or ruptured atherosclerotic plaques are the main culprit for limb ischemia and may cause claudication, chronic wounds, or necrotic lesions. In those cases, standard of care includes revascularization in addition to best medical therapy. Other sources for acute or chronic limb ischemia different from atherosclerosis are often overlooked, especially once atherosclerotic plaques have been detected. CASE REPORT We report the rare case of a patient presenting with painful necrotic ulcerations of the lower extremity due critical essential thrombocythemia that was complicated by an atherosclerotic disease. Based on the clinical presentation, 4 major differential diagnoses were initially considered: Martorell's ulcer, pyoderma gangrenosum, LEAD, and recurrent thromboembolic occlusions due to a malignant disease. Following a thorough, holistic diagnostic work-up, we identified the first diagnosis of critical essential thrombocythemia, which was aggravated by LEAD. CONCLUSIONS This case report highlights the importance of taking malignancies into consideration as a differential diagnosis in patients with repetitive arterial occlusions. With a broad variety of differential diagnoses to be considered for the presented ulcerations, this case report highlights the crucial importance of a rapid interdisciplinary approach to treat and relieve symptoms and prevent further arterial thrombotic events. The learning objective is to give a clear diagnostic work-up to navigate through the most important differential diagnoses of non-atherosclerotic conditions aggravating LEAD.