Little is known of the effects of topical application of vitamin C, glycyl-L-histidyl-L-lysine copper tri-peptide complex or melatonin as compared with topical tretinoin on the ultrastructure of skin. We were interested in determining whether any of these topical applications could enhance the repair process associated with photodamage of skin. In healthy subjects, dermal procollagen synthesis was studied after topical application of the study medications. Further investigations were done to determine possible changes in keratinocyte proliferation, keratinocyte differentiation, and cutaneous inflammation after topical application. Twenty healthy subjects were included for a period of 1 month in this study. Ten volunteers applied topical creams containing tretinoin and vitamin C to the extensor surface of their right and left thighs respectively. Ten others applied topical creams containing melatonin and the copper-binding cream to the extensor surface of their right and left thighs, respectively. Immunohistological assessment of the skin biopsies was made at baseline and after 1 month of treatment for changes in dermal procollagen synthesis, the number of Ki 67+ keratinocytes (epidermal proliferation), K-16 keratin expression (epidermal differentiation), and the number of dermal CD3+ cells (T lymphocytes). Immunohistologic assessment demonstrated a significant increase of procollagen synthesis by dermal papillary fibroblasts from baseline in 4 of 10 volunteers treated with tretinoin, 5 of 10 treated with vitamin C, 5 of 10 treated with melatonin and 7 of 10 healthy volunteers treated with the copper-binding peptide cream. Further studies in selected individuals with good dermal collagen synthesis indicated that tretinoin enhanced epidermal proliferation. A decrease in dermal CD3+ T cells with tretinoin and vitamin C application suggested that these compounds might have anti-inflammatory properties. We concluded that topical application of tretinoin, vitamin C, melatonin, and copper-binding peptide-containing creams enhanced dermal collagen synthesis, although not in all individuals. These results also open a possible application of these compounds in the repair process of cutaneous photodamage and as anti-inflammatory agents.