Recent reports have documented the development of renal thrombotic microangiopathy in patients with chronic myeloid leukemia (CML) who have undergone treatment with interferon-alpha. The pathogenesis of the renal lesion in such cases remains unclear. We report the case of a patient with chronic myeloid leukemia who developed renal failure and nephrotic syndrome while being treated with hydroxyurea and interferon-alpha. The renal biopsy showed features of chronic thrombotic microangiopathy. The patient had serologic and functional evidence of anti-phospholipid antibody. Interferon-alpha is known to cause induction of multiple autoantibodies. We propose that in the context of CML, interferon-alpha treatment can induce pathogenic anti-phospholipid antibodies that result in renal thrombotic microangiopathy. This has important implications for patients with CML receiving immune-stimulating therapy because it suggests that prospective monitoring of such patients for anti-phospholipid antibody might identify those at risk of developing thrombotic microangiopathy. Furthermore, patients with established anti-phospholipid antibody syndrome in this context might benefit from intervention such as early anticoagulation.