Magnetic resonance imaging (MRI) techniques such as magnetization transfer imaging and magnetic resonance spectroscopy (MRS) may reveal otherwise undetectable tissue damage in multiple sclerosis (MS) and can serve to explain more severe disability than expected from conventional MRI. That an inverse situation may exist where non-conventional quantitative MRI and MRS metrics would indicate less abnormality than expected from T2 lesion load to explain preserved clinical functioning was hypothesized. Quantitative MRI and MRS were obtained in 13 consecutive patients with clinically benign MS (BMS; mean age 44 +/- 9 years) despite large T 2 lesion load and in 15 patients with secondary progressive MS (SPMS; mean age 47 +/- 6 years) matched for disease duration. The magnetization transfer ratio (MTR), magnetization transfer rate (kfor), brain parenchymal fraction (BPF) and brain metabolite concentrations from proton MRS were determined. BMS patients were significantly less disabled than their SPMS counterparts (mean expanded disability status score: 2.1 +/- 1.1 versus 6.2 +/- 1.1; P < 0.001) and had an even somewhat higher mean T2 lesion load (41.2 +/- 27.1 versus 27.9 +/- 24.8 cm3; P = 0.19). Normal appearing brain tissue histogram metrics for MTR and kfor, mean MTR and kfor of MS lesions and mean BPF were similar in BMS and SPMS patients. Levels of N-acetyl-aspartate, choline and myoinositol were comparable between groups. This study thus failed to explain the preservation of function in our BMS patients with large T2 lesion load by a higher morphologic or metabolic integrity of the brain parenchyma. Functional compensation must come from other mechanisms such as brain plasticity.