Stiff-person syndrome (SPS) is a rare autoimmune neurological disorder characterized by high titers of antibodies against glutamic acid decarboxylase (GAD) and impaired GABAergic inhibitory neurotransmission. If not promptly treated, SPS progresses to disability with high risk of respiratory insufficiency; therefore, it is essential to apply the best therapeutic regimens since the beginning, both in the chronic and in the emergency setting during exacerbations. To date, there are no defined guidelines for the treatment of this rare disease. In this study, we report the case of a woman affected by refractory SPS who benefited from clonidine with immediate resolution of stiffness and SPS crisis.