The extraordinary stability of globin mRNAs permits their accumulation to over 95% of total cellular mRNA during erythroid differentiation. The stability of human alpha-globin mRNA correlates with assembly of a sequence-specific ribonucleoprotein complex at its 3'-untranslated region. A naturally occurring anti-termination mutation, Constant Spring (CS), which permits ribosomes to enter the 3'-untranslated region of the alpha-globin mRNA, results in accelerated mRNA decay. To study the mechanism of this destabilization in vivo, we established transgenic mouse lines carrying the human alphaCS gene. Relative to wild-type human alpha-globin mRNA (alphawt), alphaCS mRNA is destabilized in marrow erythroid cells. The poly(A) tails of both the alphaCS and alphawt mRNAs show a periodicity of 20-25 nucleotides consistent with phased binding of poly(A) binding proteins. However, the mean size of poly(A) tails of the unstable alphaCS mRNA is significantly shorter than that of the alphawt mRNA. Unexpectedly, the alphawt and alphaCS mRNAs are of equal stability in peripheral reticulocytes, where their respective poly(A) tails shorten coordinately. These findings demonstrate a characteristic organization of the poly(A) tail on alpha-globin mRNA which is maintained during normal and accelerated decay, a correlation between poly(A) metabolism and anti-termination-mediated accelerated mRNA turnover, and a switch in the mechanism of mRNA decay during erythroid terminal differentiation.