Efforts to fully replace the in vivo Draize skin irritation test, according to the Directive 67/548/ECC or OECD TG 404, were reinforced with the seventh Amendment of the Cosmetic Directive and the REACh regulation. In 2007, the EpiSkin test method was scientifically validated and recognized as the stand alone method to discriminate skin irritants (R38) from non-irritants (no label) according to the definition of the EU risk phrases. An ECVAM performance standards (PS) document was defined to evaluate the accuracy and reliability of other analogous test methods (ECVAM SIVS, May 2007). The present test was designed to determine the reliability and relevance of the Reconstructed Human Epidermis (RHE) model commercialized by SkinEthic. The RHE skin irritation test method consisted to topically apply topically the test substances for 42min followed by a 42h post-incubation. The main selected endpoint was the cell viability (MTT reduction), with a threshold of 50% viability. The RHE test method showed a good intra and inter-laboratory reproducibilities in a multicentric study involving three independent laboratories. The SkinEthic RHE test method showed to be relevant and reliable with a sensitivity of 90% and a specificity of 80% (MTT only) and was not improved by integrating another endpoint such as IL-1alpha. The overall accuracy was 85% resulting in the recognition of the SkinEthic RHE test method, by the ECVAM Scientific Advisory Committee in November 2008, as a stand alone replacement test method for the Draize rabbit in vivo test, as a screen, or as part of a sequential testing strategy in a weight of evidence approach, for classifying non-irritant and irritant test substances, depending on country requirements.