Substantia nigra (SN) hypoechogenicity assessed by transcranial B-mode sonography (TCS) is typical for idiopathic restless legs syndrome (RLS). Here, we investigated whether SN hypoechogenicity may differentiate between polyneuropathy (PNP) patients with and without RLS. Seventy-five patients with PNP, 65 healthy controls, and 75 patients with idiopathic RLS were investigated. A total of 41.2% patients with PNP additionally suffered from RLS. A total of 44.1% patients with PNP, 10.2% of healthy controls, and 91.2% of patients with idiopathic RLS exhibited SN hypoechogenicity. SN echogenicity did not differ significantly between PNP patients with and without RLS. Thus, TCS seems not suitable for the diagnosis of RLS in patients with PNP.