Background/purpose: Drug-induced phototoxicity is a non-immunological inflammatory skin reaction, caused by concurrent topical or systemic exposure to a specific molecule and ultraviolet radiation. Most of phototoxic compounds absorb energy particularly from UVA light leading to activated derivatives, which can induce cellular damage. This type of adverse cutaneous response can be reproduced, in vitro, using human skin models. In this study, we investigated the ability of human reconstituted epidermis Episkin® to assess skin phototoxicity of weak phototoxic compounds such as 6-methylcoumarin and ofloxacin, compared to a strong one, chlorpromazine, and two negative controls (sodium dodecyl sulphate (SDS), sulisobenzone). Methods: After 1 h incubation with five test concentrations of each chemical compound, epidermis was then exposed or not to UVA at a non-cytotoxic dose (50 J/cm2). 18 h after UVA exposure, cellular damage was evaluated measuring cytotoxicity by MTT conversion test; in addition, pro-inflammatory mediator IL-1α release was also investigated. Results: Topical pretreatment of Episkin®, with weak phototoxic compounds induced, after UVA exposure, a dose-dependent decrease in cell viability, in concordance with an increasing IL-1α release. Moreover, compared to chlorpromazine, the lower IL-1α release observed with 6-methylcoumarin and ofloxacin could be linked to their weak phototoxic potential. Conclusion: Human reconstituted epidermis Episkin® can be useful to study in vitro the onset of cutaneous phototoxic reactions and particularly to identify weak phototoxic compounds.