Erythropoietin (EPO) is a major hormone involved in regulation and maintenance of a circulating erythrocyte mass and control of erythropoiesis. We targeted the expression of recombinant human EPO to the mammary gland of transgenic mice using 1.6 kb caprine [i-lactoglobulin promoter. Three transgenic lines with a successful germ line transmission of the transgene were obtained. Transgenic animals showed an increased hematocrit and red blood cell counts with splenomegaly. The phenotype was observed in both male and female mice of all three transgenic lines. A high level of EPO in the sera of polycythemic mice was detected by radioimmunoassay indicating that the phenotypes were direct results of elevated EPO levels in transgenic mice. Apparent ectopic expression of EPO in the transgenic mice appeared to be due to the lack of tissue specificity of the promoter used. Nontheless, a similarity between phenotypes of transgenic mice and human polycythemia indicates that the transgenic animals can be utilized as a disease model for polycythemia. Employment of a longer regulatory element of the caprine β-lactoglobulin gene may improve mammary gland-specific expression of the transgene.