β-Elimination of drugs tethered to macromolecular carbamates provides a platform for drug half-life extension. However, the macromolecular Michael acceptor products formed upon drug release can potentially react with biological amines and thiols and may raise concerns about safety. We desired to mitigate this possibility by developing linkers that have predictable rates of β-elimination but suppressed rates of nucleophilic addition to their Michael acceptor products. We prepared Michael acceptor products of β-eliminative linkers that contained a methyl group at the Cβ carbon or a gem-dimethyl group at the Cγ carbon and studied the kinetics of their reactions with the most prevalent biological nucleophiles-amine and thiol groups. Aza-Michael reactions with glycine are slowed about 20-fold by methylation of the β-carbon and 175-fold with a gem-dimethyl group at the γ-carbon. Likewise, addition of the glutathione thiol to γ-gem-dimethyl Michael acceptors was retarded 7-24-fold compared to parent unsubstituted linkers. It was estimated that in an in vivo environment of ∼0.5 mM macromolecular thiols or ∼20 mM macromolecular amines-as in plasma-the reaction half-life of a typical Michael acceptor with a γ-gem-dimethyl linker could exceed 3 years for thiols or 25 years for amines. We also prepared a large series of γ-gem-dimethyl β-eliminative linkers and showed excellent structure-activity relationships of elimination rates with corresponding unsubstituted parent linkers. Finally, we compared the first-generation unsubstituted and new gem-dimethyl β-eliminative linkers in a once-monthly drug delivery system of a 39 amino acid peptide. Both linkers provided the desired half-life extension of the peptide, but the Michael acceptor formed from the gem-dimethyl linker was much less reactive. We conclude that the γ-gem-dimethyl β-eliminative linkers provide high flexibility and greatly reduce potential reactions of Michael acceptor products with biologically important nucleophiles.