Somatomedin-C/insulin-like growth factor I (SM-C/IGF-I) binds to both cultured keratinocytes trypsinized to single-cell suspensions and fresh epidermal sheets derived from 1 M NaBr-treated 6-mm punch biopsies. A gradual increase of 1–4% in specific binding of SM-C/IGF-I to fresh epidermal sheets was observed during a 5-hour incubation period at 15°C. The human keratinocyte SM-C/IGF-I receptor was isolated by polyacrylamide gel electrophoresis after cross-linking with iodinated SM-C/IGF-I and migrated at 135,000 daltons under reducing conditions. Both a partially purified preparation of SM-C/IGF-I, as well as recombinant DNA-derived thr-59-SM-C/IGF-I (25–100 ng/ml), stimulated keratinocyte replication in a serum-free system, with an approximately equivalent effect as insulin (10 μg/ml). Since fibroblasts produce SM-C/IGF-I, our data suggest that some dermal-epidermal interactions in diseases such as psoriasis may be mediated, in part, by SM-C/