Several podophyllotoxin-related cyclolignans, either lacking the lactone ring or the methylenedioxy grouping, have been prepared and evaluated for their immunosuppressive (IMS) activity in the mouse allogeneic MLR in vitro test and in the in vivo techniques Graft vs Host Reaction (GVHR) and Skin Grafting (SG). The results obtained show that three cyclolignans fairly prevent splenomegaly in comparison with control animals and also promoted tolerance to grafting, being the first time that the in vivo IMS activity of cyclolignas is reported.