Purpose To perform a direct metabolic comparison of chronic lesions and diffusely injured normal-appearing white matter (NAWM) in multiple sclerosis (MS). Materials and Methods In this institutional review board-approved study, with the written informed consent of all patients, two-dimensional magnetic resonance spectroscopic imaging data in 46 patients with relapsing-remitting MS (median disease duration, 0.8 year) were analyzed by using the spectral quantification tool LCModel. Metabolic patterns were evaluated for non-gadolinium-enhancing chronic lesions and the corresponding contralateral NAWM. The sensitivity of the method was assessed by reproducing the known metabolic differences between cortical gray matter (GM) and NAWM. In addition to individual spectra, averaged spectra were calculated by accumulating free induction decays over all subjects to yield an increased signal-to-noise ratio (SNR), and in turn, to allow improved curve fitting as demonstrated by lower error bounds for low-concentration metabolites. Metabolite concentrations were statistically tested for intraindividual differences (paired t tests) to avoid effects resulting from variations in disease severity or treatment. Results Differences between the metabolite concentrations in the NAWM and the cortical GM were highly significant (P < .001), demonstrating the reliability of the spectral analysis used here. The spectral patterns of the individual and averaged spectra of chronic lesions and NAWM were qualitatively very similar at visual inspection. Furthermore, in the quantitative comparison, the estimated metabolite concentrations showed only slight differences (P > .07). Owing to increased SNRs in the averaged spectra compared with individual spectra (eg, for chronic lesions, 63 vs 28.4 ± 4.1), it was possible to reliably (Cramér-Rao lower bound [CRLB], <20%) estimate scyllo-inositol levels with a CRLB of 14%. Conclusion These findings revealed that NAWM exhibits the same metabolic changes as chronic white matter lesions, even very early in the disease course, further supporting the view that such lesions may not be as relevant as widely assumed. © RSNA, 2016.