A novel series of analogs of 1,25-dihydroxyvitamin D₃, the hormonally active metabolite of vitamin D₃, characterised by the presence of a trans-fused decalin CD-ring system, possesses surprising biological activities in combination with specific structural modifications in the flexible parts of the molecule, when compared with the natural hydrindane derivatives. (1) A large difference in biological activity is observed between the 20-epimeric trans-decalin analogs that follows a pattern opposite to what is usually observed for the natural ring size. (2) Several trans-decalin analogs that are modified in the seco-B-ring region, including previtamin derivatives, possess a pronounced vitamin D-like activity, whereas the corresponding hydrindane derivatives are inactive. The molecular origin of this behavior is still under study.