Intrathecal (i.t.) drug application is accepted as a highly effective treatment option for various neurological conditions. Technical risks and potentially dangerous complications require appreciation. We present the case of a patient treated with i.t. recombinant, human brain-derived neurotrophic factor (rhBDNF) as an experimental therapy for amyotrophic lateral sclerosis (ALS). Five days after starting the i.t. drug infusion, she complained of severe headache and nausea. Radiological studies suggested the catheter was located within the epi-arachnoidal space. A deposit of more than 10 ml secluded from the subarachnoidal space was found within this space. I.t. contained a high concentration of the applied drug. Revision of the catheter resulted in complete recovery from symptoms and i.t. infusion could be continued. The epi-arachnoidal positioning of a spinal catheter is a potential cause for treatment failure. If the membrane around the fluid deposit ruptures, the drug could be released into the subarachnoidal space, with the consequence of a potentially life-threatening complication.