Significance Proteolysis targeting chimera (PROTAC)-based protein degradation is an emerging field that holds significant promise for targeting the “undruggable” proteome: the vast majority of the proteins that do not exhibit enzymatic activity and are thereby not amenable to classical inhibition. Despite significant progress, a thorough mechanistic characterization of biochemical determinants that underpin efficient PROTAC activity is lacking. Here we address one such question: Is positive cooperativity necessary for potent protein degradation? Through a collection of independent techniques, we show that within a Bruton’s tyrosine kinase/cereblon PROTAC system, potent knockdown correlates with alleviation of steric clashes in the absence of thermodynamic cooperativity. This result broadens the scope of PROTAC applications and affects fundamental design criteria across the field.