Long-term loss of fetal blood can occur with fetomaternal hemorrhage, vasoprevia, or placental previa. Our objective was to determine the effects of progressive fetal blood loss over 10 days on fetal plasma erythropoietin (EPO) concentration and its relationship to arterial PO₂, hematocrit, and the volume of blood loss. Late-gestation fetal sheep (n = 8) were hemorrhaged daily at a rate of 1 ml/min over 10 days. The extent of hemorrhage differed in each fetus and ranged from 30 to 80 ml/day, with the cumulative volume removed ranging from 78 to 236 ml/kg estimated fetal weight. Four fetuses served as time controls. EPO concentration measurements were by radioimmunoassay. Statistical analyses included regression, correlation, and analysis of variance. We found that EPO and arterial PO₂ were unchanged until the cumulative hemorrhage volume exceeded 20-40 ml/kg. Once this threshold was exceeded, plasma EPO concentration increased progressively throughout the study and averaged 14.3 ± 3.2 times basal values on day 10. EPO concentration, arterial PO₂, and hematocrit changes were related curvilinearly to cumulative hemorrhage volume (P < 0.01), whereas the relationship between plasma EPO and arterial PO₂ was log linear (P < 0.001). We conclude that 1) fetal plasma EPO concentration and arterial PO₂ are insensitive to a slow, mild-to-moderate blood loss over several days; 2) unlike the rapid return of EPO to normal within 48 h after acute hemorrhage, fetal EPO concentration undergoes a progressive increase with moderate-to-severe blood loss over several days; 3) the long-term hemorrhage-induced changes in EPO are best correlated with arterial PO₂; and 4) the fetal EPO response to hemorrhage does not appear to be limited by the fetus's ability to produce EPO.