We tested the hypotheses that ethanol sensitivities of muscle and liver can be discerned in the initial periods of ethanol exposure, especially when acetaldehyde levels are markedly raised with cyanamide, an aldehyde dehydrogenase inhibitor. To test this, we measured cholesterol hydroperoxides in soleus (Type I) and plantaris (Type II) muscle in four groups of rats acutely (i.e., 2.5 h) exposed to: [S] saline (control), [Cy] cyanamide, [EtOH] ethanol, or [Cy + EtOH] cyanamide + ethanol. Comparative reference was also made to the response of the liver. After 2.5 h, ethanol alone significantly increased 7 alpha-hydroperoxycholest-5-en-3 beta-ol (7 alpha-OOH) and 7 beta-hydroperoxycholest-5-en-3 beta-ol (7 beta-OOH) levels in plantaris muscle. Identical qualitative effects were seen in rats treated with cyanamide + ethanol, but there was no discernible difference between groups [EtOH] and [Cy + EtOH]. In both the soleus muscle and liver, none of the treatments with either ethanol or cyanamide + ethanol had any effect on any of the measured parameters. This is the first report of a differential response of 7 alpha-OOH and 7 beta-OOH in Type II, compared to Type I predominant muscles, and the first time that muscle has been shown to be more sensitive than the liver in terms of its lipid marker response to oxidative stress. Perturbations in the muscle membrane lipid domain may contribute to impairment of muscle in alcoholism.