Multicenter proton magnetic resonance spectroscopic imaging (MRSI) studies were performed on 58 primary progressive multiple sclerosis (PPMS) patients from four centers for investigating the efficacy of glatiramer acetate (GA) treatment. These patients were drawn from 943 subjects who participated in the PROMiSe trial. In these MRSI studies, patients were followed over a period of 3 years. MRSI data were acquired by all the centers using the same pulse sequence, and spectral analysis was performed at a single site using a customized analysis software package. Quantitative metabolite ratios, N-acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr, were compared between GA-treated and placebo-treated PPMS patients. There was no significant difference in metabolite ratios between GA-treated and placebo-treated patients. The difference in metabolite ratios between the normal-appearing tissues (NAT) and lesion-containing regions (LCR) in GA treated patients was not significantly different from placebo treated patients. Strong lipid resonances, even in the absence of lesions, were observed on MRSI data in both gray matter and white matter in placebo- and GA-treated PPMS patients. No significant difference in number of patients with lipids between the two groups over a period of 3 years was found.