We described dually targeting CRBN-VHL PROTACs, developed with the aim of investigating the relative ability of CRBN and VHL E3 ligase to induce degradation of one other. Among the three series of compounds developed, we observed preferential degradation of one ligase i.e. CRBN other the other one (VHL) with some of the compounds from two of the series. The most potent PROTAC, compound 14a, induced CRBN degradation with high potency (DC 50 of 200 nM) and to profound levels (D max of up to 98%) and rapidly (within 1 h of treatment). Further structure-activity relationships could help to better understand and improve the already high potency and efficiency of CRBN degradation achieved with 14a.