SUMMARYEtretinate and isotretinoin were compared with respect to their clinical effects and changes in serum lipoprotein concentrations.Sixteen patients with hyperkeratotic and pustular disorders of hands and feet (mainly palmoplantar pustulosis) underwent a double‐blind cross‐over study. The daily doses of etretinate and isotretinoin were 50 and 40 mg, respectively. Each drug was given for 2 months with a 2‐month intermission.The clinical score was reduced both by isotretinoin (P<0.05) and etretinate (P<0.001). Both drugs affected the lipoprotein concentrations. Isotretinoin increased the cholesterol concentration in low‐density lipoprotein (LDL) by 20% and the triglyceride concentration in very low‐density lipoprotein (VLDL) by 35%, but decreased the high‐density lipoprotein cholesterol by 12%. Etretinate elevated LDL‐cholesterol by 10%. These changes had reverted to normal 8 weeks after the end of treatment.The data suggest that in the diseases studied, etretinate is preferable to isotretinoin with regard to both clinical effect and serum lipid