Stiff-person syndrome (SPS), formerly termed stiff-man syndrome, is characterized by muscular rigidity and episodic spasms mainly involving the trunk and lower limbs. The typical form is an autoimmune disease characterized by progressive axial rigidity, predominantly involving the paraspinal and abdominal muscles, along with hyperlordosis of the lumbar spine, spontaneous or stimulus sensitive disabling muscle spasms of the abdominal wall, lower extremities and other proximal muscles. Ninety-five percent of patients had GAD-65 and 89% had islet cell antibodies (ICA). A sizeable number of patients also have other antibodies such as those against glycine receptor and glycine transporter 2. SPS associated with neoplasms tends to involve the upper limbs and neck and cranial nerves. Patients with carcinoma of the breast or lung (oat cell carcinoma) may develop SLS with high titers of anti-amphiphysin antibodies. This chapter illustrates the use of botulinum toxin (BoNT) in the treatment of SPS, along with anatomical illustrations demonstrating the typical involved musculature, and approach to injection with botulinum neurotoxin, with tabulated dosing recommendations for the various BoNT formulations.