The metabolic response of the rhesus macaque brain during acute simian immunodeficiency virus (SIV) infection was investigated with in vivo ¹H MR spectroscopy. Fifteen rhesus macaques were studied before inoculation, and once or twice after infection. In all, 13/15 macaques had elevations of Cho/NAA at 11–13 days postinoculation (dpi); all 10 macaques measured after 13 dpi had subsequent reduction of this ratio (ANOVA, P < 10^‐6). There were significant increases in Cho/Cr (20%, P = 0.04) and MI/Cr (14%, P = 0.003) at 11 dpi. At 13 dpi a 7.7% decrease (P = 0.02) in NAA/Cr was observed, while Cho/Cr was no longer significantly different from baseline. At 27 dpi Cho/Cr was decreased to 18% (P = 0.004) below preinoculation values, while NAA/Cr and MI/Cr were at baseline values. Absolute concentrations of Cho, MI, and NAA showed a similar time course, with no observed changes in Cr. There was a strong correlation between Cho/Cr change and plasma viral load (r_s = 0.79, P < 0.01). Acute SIV produces extensive metabolic abnormalities in the brain, which may reflect inflammation and neuronal injury, which are reversed with immunological control of the virus. Similar events are likely to occur in acutely HIV‐infected people, and may explain the neurobehavioral symptoms associated with acute HIV infection. Magn Reson Med 51:1108–1114, 2004. © 2004 Wiley‐Liss, Inc.