During the last 10 years we treated 39 children with severe keratinization disorders with the aromatic retinoid etretinate. Six of these children were followed-up for 8–9 years. Mucocutaneous serum enzymatic and lipid side effects of etretinate were mild, transient and well tolerated. Osseous side effects were present after 4–6 years in all our 6 patients on prolonged retinoid therapy. Asymptomatic osseous neoformation and osseous reabsorp-tion in the absence of calcium, phosphate, and alkaline phosphatase serum alterations have been observed. The growth and development curves and the sexual development of our patients (with exception of a patient with Rud’s syndrome) have been normal. Osteoporosis and slender diaphysis were often present at initiation of therapy. On the basis of our findings and recent reports of the literature we suggest restricting retinoid therapy of keratinizing disorders in children to conditions severe enough to be physically, psychologically or socially incapacitating. In an attempt to reduce the risk of chronic toxicity and possibly to allow regression of initial bone alterations, intermittent therapy and combination therapy are recommended.