The therapeutic use of tumor necrosis factor a (TNFa) antagonists has added a highly effective treatment in the field of inflammatory musculoskeletal, skin, and bowel diseases. Most of the side effects of these very potential agents, like infections or skin reactions, were predictable; the development of psoriatic lesions was not, as they are very successfully used to treat psoriasis and psoriatic arthritis, too. There is a number of cases of anti-TNFa-induced psoriatic lesions in the literature, some of them developing with the use of two agents in the same patient, clearly suggesting a class effect. We report an additional series of 12 cases from a total of 300 patients (>800 patient years) and hypothesize on several mechanisms for the explanation of this paradoxical phenomenon namely, local action of TNF, dysregulation of regulatory T cells, or, finally, imbalance between TNF and interferon-a locally. Further studies are needed to elucidate the exact pathogenesis of these manifestations, so that the use of these agents will not only have changed the course of diseases like rheumatoid arthritis or ankylosing spondylitis but may also aid our in depth understanding of the underlying process of disease.