Human immune system (HIS) mouse models can be valuable when cross-reactivity of drug candidates to mouse systems is missing. However, no HIS mouse models of psoriasis have been established. In this study, it was investigated if imiquimod (IMQ) induced psoriasis-like skin inflammation was driven by human immune cells in human FMS-related tyrosine kinase 3 ligand (hFlt3L) boosted (BRGSF-HIS mice). BRGSF-HIS mice were boosted with hFlt3L prior to two or three topical applications of IMQ. Despite clinical skin inflammation, increased epidermal thickness and influx of human immune cells, a human derived response was not pronounced in IMQ treated mice. However, the number of murine neutrophils and murine cytokines and chemokines were increased in the skin and systemically after IMQ application. In conclusion, IMQ did induce skin inflammation in hFlt3L boosted BRGSF-HIS mice, although, a limited human immune response suggest that the main driving cellular mechanisms were of murine origin.