EPC-1/PEDF (early population doubling level cDNA-1/retinal pigmented epithelium-derived factor) is a single-copy, quiescence-specific gene that is transcribed into a 1.5 kb mRNA and then translated into a 50 kDa secreted protein that is a potent inhibitor of angiogenesis. EPC-1 expression has been detected in a number of cultured cell lines, including lung and skin fibroblasts, retinal pigmented epithelial cells, and endometrial stromal fibroblasts. Furthermore, its expression has been shown to decline during replicative aging of these cells in culture. In this report, we describe our examination of the age-related changes in EPC-1 expression in situ in skin sections from donors of different ages. EPC-1 mRNA is detected primarily in the dermal layer of the skin and its expression declines with increasing donor age. This decline is statistically significant between young (less than 31 years old) and middle-aged (between 30 and 60 years old) donors, with the decline becoming less dramatic at older ages. This age-related decline in the expression of an angiogenic inhibitor contributes to the imbalance of angiogenic modulators that is observed during aging. In fact, this decline may reflect a compensatory change to help reverse the decline of angiogenesis marked by reduced abundance of microvessels. This downregulation of an angiogenesis inhibitor may, in turn, play a critical role in the development of diseases caused by abnormal vascularization. The potential role of the age-associated decline in EPC-1 expression in tissue remodeling and in the development of skin diseases with excessive angiogenesis may provide new insights into disease prevention.