Isotretinoin (IT) is used orally for the treatment of severe acne that has not responded to other measures. IT has also been tried in a number of other skin disorders and in some forms of neoplastic disease. It has obvious adverse side effects in oral administration. The most common is dryness of the mucous membranes, visual disturbances, skeletal hyperostosis, and musculoskeletal symptoms. Elevation of serum triglycerides, blood glucose and hepatic enzymes has also been reported (1, 2). However, topical preparations of IT are available, such as creams and gels that show systemic absorption. The topical utility of IT is strongly limited by several disadvantages, such as skin irritation, very low water solubility, and high instability in the presence of light, air and heat. The aim of this study was to develop new solid lipid nanoparticles of isotretinoin (IT-SLNs) and evaluate the ability of IT-SLNs to improve photostability, reduce skin permeation and irritating effects. IT-SLNs were prepared by the hot high pressure homogenization method. Size, zeta potential and morphological characteristics of the preparations were assessed by transmission electron microscopy (TEM) and thermotropic properties with differential scanning calorimetry (DSC). IT-SLNs had a small average diameter of 74.05 ± 8.91 nm and high encapsulation efficiency (EE) of 80.6 ± 1.2 %. The results showed that the entrapment of IT into SLNs reduced significantly its photodegradation. The in vitro permeation data showed that IT-SLNs can accumulate in the different layers of the skin and prevent systemic uptake of IT in mouse skin. IT-SLNs also significantly increased IT accumulation in the different layers of the stratum corneum of human skin. IT-SLN formulation was significantly less irritating compared to commercial IT-GEL, which shows its potential for improving skin tolerability and being a carrier for topical delivery of IT.