Tissue inhibitor of metalloproteases (TIMP) is a major regulator of extracellular matrix synthesis and degradation. Moreover elevated tissue inhibitor of metalloproteases levels are found in the blister fluid of many diseases, suggesting that tissue inhibitor of metalloproteases plays a role in epidermal and dermal wound healing. The aim of this work was to study the effects of human recombinant tissue inhibitor of metalloproteases in a skin equivalent model used to evaluate the effects of drugs on epidermal and dermal components. Planimetry, DNA assays, and histologic studies showed that tissue inhibitor of metalloproteases enhanced the growth of normal human keratinocytes on dermal equivalent. Thus, the extracellular matrix regulator tissue inhibitor of metalloproteases also stimulates the growth of keratinocytes. Identity of the gene encoding tissue inhibitor of metalloproteases and Erythroid Potentiating Activity (EPA) has been reported. The effects of tissue inhibitor of metalloproteases on keratinocytes described herein are reminiscent of the stimulating effect of erythroid potentiating activity on the growth of erythroid precursors.