Neurologic disease is reported to occur in just 10% of patients with mixed connective tissue disease (MCTD). Most commonly, this is manifested by mild trigeminal neuralgia. This report details the clinical and neuropathologic findings of transverse myelitis in a patient with MCTD. Neurologic features include progressive areflexic paraplegia with loss of bowel and bladder function. Neuropathologically there was thinning of the thoracic cord, widespread loss of axons and myelin sheaths, reactive astrocytosis, macrophage formation, vascular thickening with perivascular chronic inflammatory cell infiltration, and calcium deposits. This case demonstrates that severe neurologic disease unresponsive to therapy can occur in MCTD.