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<h3>Objective:</h3> To establish cerebral metabolic features associated with the A3243G mitochondrial DNA mutation with proton magnetic resonance spectroscopic imaging (¹H MRSI) and to assess their potential as prognostic biomarkers. <h3>Methods:</h3> In this prospective cohort study, we investigated 135 clinically heterogeneous A3243G mutation carriers and 30 healthy volunteers (HVs) with ¹H MRSI. Mutation carriers included 45 patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); 11 participants who would develop the MELAS syndrome during follow-up (converters); and 79 participants who would not develop the MELAS syndrome during follow-up (nonconverters). The groups were compared with respect to MRSI metabolic indices of 1) anaerobic energy metabolism (lactate), 2) neuronal integrity (<i>N</i>-acetyl-l-aspartate [NAA]), 3) mitochondrial function (NAA; lactate), 4) cell energetics (total creatine), and 5) membrane biosynthesis and turnover (total choline [tCho]). <h3>Results:</h3> Consistent with prior studies, the patients with MELAS had higher lactate (<i>p</i> &lt; 0.001) and lower NAA levels (<i>p</i> = 0.01) than HVs. Unexpectedly, converters showed higher NAA (<i>p</i> = 0.042), tCho (<i>p</i> = 0.004), and total creatine (<i>p</i> = 0.002), in addition to higher lactate levels (<i>p</i> = 0.032), compared with HVs. Compared with nonconverters, converters had higher tCho (<i>p</i> = 0.015). Clinically, converters and nonconverters did not differ at baseline. Lactate and tCho levels were reliable biomarkers for predicting the risk of individual mutation carriers to develop the MELAS phenotype. <h3>Conclusions:</h3> ¹H MRSI assessment of cerebral metabolism in A3243G mutation carriers shows promise in identifying disease biomarkers as well as individuals at risk of developing the MELAS phenotype.