Purines are extracellular nucleotides that have long-term effects on keratinocyte proliferation, differentiation and death through P2Y(1), P2Y(2), P2X(5) and P2X(7) receptors. This study examined changes in expression of these P2 receptors on lower leg epidermal keratinocytes in control and chronic venous insufficiency (CVI) states. Lower limb skin biopsies from CVI (CEAP classification 4a and 4b) and control skin were immunostained for the above P2 receptor subtypes and epidermal area was calculated. Our results with CVI show an increase in P2Y(1) and P2Y(2) receptor expression in basal and spinosal layers of the epidermis and an increase of P2X(5) receptors mainly in the spinosal layer and extending further into the stratum granulosum. In contrast, P2X(7) receptors were reduced in the stratum corneum in CVI. In conclusion, a thinner epidermis was found in CVI, which might be the result of the changes in expression of P2Y and P2X receptors on keratinocytes: that is, increased proliferation via P2Y(1) and P2Y(2) receptors and reduced P2X(7) receptor-mediated cell death opposed by a dominant decrease in cell numbers as a result of increased P2X(5) receptor-mediated differentiation (which is in effect antiproliferative). Thus, increased keratinocyte P2X(5) receptor activity may, in part, be accountable for epidermal thinning in CVI.