Although excessive alcohol consumption is known to elevate the mean cell volume (MCV) of erythrocytes, the relationships among the intensity of ethanol exposure, the generation of abnormal red blood cell indices, and the underlying pathogenic mechanisms have remained unclear. The authors examined 105 alcoholics with a wide range of ethanol consumption (40–500 g of ethanol/day), 62 moderate drinkers (mean consumption 1–40 g/day), and 24 abstainers, who underwent detailed interviews, measurements of blood cell counts, markers of liver status, and circulating antibodies against ethanol-derived protein modifications. Follow-up information was collected from healthy volunteers with detailed records on drinking habits. Data from the NORIP project for laboratory parameters in apparently healthy moderate drinkers or abstainers (n = 845) were used for reference interval comparisons. The highest MCV ( P < 0.001) and mean cell hemoglobin (MCH) ( P < 0.01) occurred in the alcoholics. However, the values in the moderate drinkers also responded to ethanol intake such that the upper normal limit for MCV based on the data from moderate drinkers was 98 fl, as compared with 96 fl from abstainers. Follow-up cases with carefully registered drinking habits showed parallel changes in MCV and ethanol intake. Anti-adduct IgA and IgM against acetaldehyde-induced protein modifications were elevated in 94% and 64% of patients with high MCV, respectively, the former being significantly less frequent in the alcoholics with normal MCV (63%) ( P < 0.05). The data indicate dose-related responses in red blood indices upon chronic ethanol consumption, which may also be reflected in reference intervals for hematological parameters in health care. Generation of immune responses against acetaldehyde-modified erythrocyte proteins may be associated with the appearance of such abnormalities.