We enrolled 11 patients with secondary progressive MS in a randomized single-masked cross-over study of plasma exchange (PE) in combination with azathioprine 2 mg/kg. PE was performed once a week for 4 weeks and thereafter every second week for 20 weeks (14 treatments). Eight patients completed the whole trial, and three patients discontinued the trial, two during the run-in period of azathioprine treatment and one at the introduction of PE. The primary efficacy variables were the number of gadolinium-enhancing lesions and the occurrence of new enhancing lesions on serial MRI performed every 3 weeks during the PE and the control period. Secondary efficacy variables were the total MS lesion load on T2-weighted MRI, multimodal evoked potentials, and clinical neurologic ratings. No significant differences were found regarding the number of enhancing lesions or occurrence of new enhancing lesions in the two periods. Although the total MS lesion load on MRI was significantly lower (p < 0.02) and central motor conduction times decreased significantly (p < 0.05) during PE, this small study did not provide sufficient evidence for a significant beneficial effect of PE or encourage a subsequent large randomized parallel group study.