Acute motor-sensory axonal neuropathy (AMSAN) is an axonal variant of Guillian-Barré syndrome (GBS) that presents with acute ascending quadriparesis. This has generally been described in association with Campylobacter jejuni infections or with antiganglioside antibodies. Known cases have shown a slow recovery and a poor prognosis. We report a case with clinical and electrophysiological evidence of AMSAN in association with active systemic lupus erythematosus (SLE) and anticardiolipin antibodies but not the other associations, with a rapid response to combination immunosuppressant and intravenous immunoglobulin (IVIg) therapy. The association between AMSAN and SLE has not been previously described. This case illustrates that early recognition and the utilization of electrophysiologic techniques may be beneficial in the diagnosis and management of GBS associated with SLE. Fulminant or rapidly progressive cases should be managed in specialized intensive care units. Combination therapy of immunosuppressants and IVIg may be beneficial in nonvasculitic axonal radiculoneuropathies associated with SLE, resulting in good outcomes.