C57BL/6N mice fed zidovudine in their drinking water develop selective hyperpigmentation of the tails and footpads. Zidovudine-fed and identical control mice were observed and sequential biopsy specimens were obtained. Routine light microscopy, electron microscopy, and image analysis of unstained biopsy specimens were used to evaluate the extent, nature, and amount of cutaneous hyperpigmentation.Beginning at day 14 selective hyperpigmentation of the tails and footpads of the mice was noted. Histologic evaluation revealed a gradual increase in melanin, beginning in the lower levels of the epidermis, with eventual pigmentation of the stratum corneum. Electron microscopy demonstrated a sixfold increase in melanosomes in the tail skin of the zidovudine-fed mice. Using image cytometry, melanin was quantitatively shown to increase, paralleling the clinically apparent hyperpigmentation. The hyperpigmentation was reversible on discontinuation of zidovudine.This animal model parallels the human in developing reversible and selective hyperpigmentation on administration of zidovudine. In this model the increased pigmentation is due to increased numbers of melanosomes within epidermal keratinocytes. Image cytometry may be useful in semiquantitatively studying the pathogenesis of various disorders of hyperpigmentation.