Background: Intravenous immunoglobulin (IVIg) has traditionally served as the primary treatment for Guillain-Barré syndrome (GBS), reserving plasmapheresis for severe cases or as an adjunctive therapy with uncertain outcomes. Currently, there is no robust recommendation supporting the utility of therapeutic plasma exchange (TPE) following IVIg treatment failure. Case Report: In this report, we present a case of severe GBS accompanied by respiratory failure necessitating mechanical ventilation. Nerve conduction studies and electromyography (EMG) findings indicated a profound hyperacute motor sensory axonal neuropathy phenotype of GBS. Despite an initial course of IVIg at a dosage of 0.4 g/kg administered over five consecutive days, the patient exhibited no improvement. However, a notable turnaround in the patient's condition was observed following TPE. Conclusion: This case report underscores the potential benefit of TPE as a viable treatment option for select patients who fail to respond to immunoglobulin therapy, shedding light on its effectiveness in such challenging cases of GBS.