When evaluating the tolerability profile of interferons, the authors focus their attention on peripheral neuropathy, by assessing the epidemiological, pathogenetic, clinical, and outcome aspects, in relation with the administration of these drugs and the concurrent increase of risk factors associated with underlying diseases (including chronic viral hepatitis, solid organ malignancies, hematological disorders, autoimmune diseases, HIV infection). Even though it is often impossible to exclude a direct or indirect interferon-associated pathogenetic pathways in the occurrence of peripheral neuropathies, predominatly through immune-mediated mechanisms, the episodes reported by the international literature are steadily on the rise, paralleling the enlargement of therapeutic indications, and the availability of novel interferon formulations for clinical use. The increased indications of interferons in a broadening spectrum of clinical disorders, and especially their use in chronic hepatitis, recommend a strict monitoring of all possible adverse events, in order to reach a better epidemiological, pathogenetic, and clinical awareness of clinical events which are still infrequent, but potentially severe, such as those involving the peripheral nervous system.