Despite contrary recommendations by expert opinion and international guidelines phenobarbital remains the most widely prescribed anticonvulsant worldwide. Although associated connective tissue disorders were described in a timely way after its introduction, the association between plantar fibromatosis—also called Ledderhose syndrome—and phenobarbital seems not to be well known in general. Our case series uniquely demonstrates that continuous phenobarbital treatment leads to recurrent plantar fibromatosis and may result in long-term disability and numerous unnecessary operations. In general, the association between connective tissue disorders and phenobarbital most prominently appears in adult patients of northern European descent. However, our case series and data from the literature suggest that patient groups less susceptible to connective tissue disorders may as well develop Ledderhose syndrome or other associated syndromes as Dupuytren's contractures, frozen shoulder, Peyronie's disease or complex regional pain syndrome in the course of phenobarbital treatment.