New daily persistent headache is a continuous, unremitting headache, notorious for its unresponsiveness to aggressive medical interventions. The underlying pathophysiology of new daily persistent headache is poorly understood resulting in unending, chronic pain. However, a prior study identified elevated tumor necrosis factor alpha within the cerebral spinal fluid of new daily persistent headache patients. Herein, we report on a patient who suffered with headache for 6 years failing to respond to over 20 different medical treatments, but found drastic improvement and eventual resolution with Venlafaxine. This drug binds to the 5-HT receptor inhibiting tumor necrosis factor alpha signaling. Therefore, we hypothesize a chronic inflammatory mechanism driving new daily persistent headache pathology.