Human type IV collagen discs were found to support proliferation and adhesion of rabbit corneal epithelial cells in tissue culture. To assess the biocompatibility of this synthetic collagen for epikeratoplasty, seven eyes of seven rhesus monkeys underwent epikeratoplasty with lenticules made of human type IV collagen. Eye rubbing by the animals expulsed two of the lenticules and caused failure of two to epithelialize completely. The remaining three lenticules epithelialized, remained clear, and caused no adverse effects on the eye. Two of these lenticules developed focal areas of subepithelial thinning 3 months postoperatively and the third lenticule has remained stable for 30 months. The presence of epithelial attachment components at the epithelial-lenticule interface was demonstrated by immunolocalization. Histopathologic and ultrastructural examination revealed focal areas of epithelial invasion and degradation of the lenticule. Neutral proteases were detected in the thinning region of one specimen. Human type IV collagen supports epithelialization in vivo and may have potential as a biomaterial for epikeratoplasty, but the stability of the material must be improved.