Alpha-dystroglycan (alpha-DG) plays a crucial role in maintaining the stability of muscle cell membrane. Although it has been shown that the N-terminal domain of alpha-DG (alpha-DG-N) is cleaved by a proprotein convertase, its physiological significance remains unclear. We show here that native alpha-DG-N is secreted by a wide variety of cultured cells into the culture media. The secreted alpha-DG-N was both N- and O-glycosylated. Finally, a small amount of alpha-DG-N was detectable in the normal human serum. These observations indicate that the cleavage of alpha-DG-N is a widespread event and suggest that the secreted alpha-DG-N might be transported via systemic circulation in vivo.