Treatment approaches are rare for chronic progressive patients with multiple sclerosis (MS). Objective was to evaluate the clinical benefit of repeated intrathecal application of the sustained release steroid triamcinolone acetonide or the administration of mitoxantrone (MIX) in 2 similar cohorts of chronic progressive patients with MS in an open-label fashion. Expanded Disability Status Scale scores significantly decreased after the first 6 intraspinal triamcinolone acetonide injections, which were performed every third day, and then remained stable. Walking distance significantly increased and did not reduce until the end of the 1-year-long trial period. Mitoxantrone treatment did not improve the Expanded Disability Status Scale score; however, no further significant deterioration appeared. Walking distance did not significantly decrease. Both treatment regimens were safe; the patients experienced nearly no adverse effects. Triamcinolone acetonide application provided a clinical benefit, whereas MIX administration prevented further worsening of MS symptoms. We stress that only specialists with a broad experience in intraspinal triamcinolone acetonide application and MIX administration should perform both kinds of therapy only after a careful information and risk-benefit evaluation in cooperation with the patient. Future trials will show the efficacy of combination of both treatment approaches in chronic progressive patients with MS.