Michael-addition of a thiol to a maleimide is commonly used for bioconjugation of drugs to macromolecules. Indeed, both current FDA-approved antibody-drug conjugates-Brentuximab vedotin and Trastuzumab emtansine-and one approved PEGylated conjugate-Cimzia-contain a thiol-maleimide adduct. However, the ultimate in vivo fate of such adducts is to undergo disruptive cleavage by thiol exchange or stabilizing ring opening. Therapeutic efficacy of a conjugate can be compromised by thiol exchange and the released drug may show toxicities. However, if the succinimide moiety of a maleimide-thiol conjugate is hydrolyzed, the ring-opened product is stabilized toward cleavage. We determined rates of ring-opening hydrolysis and thiol exchange of a series of N-substituted succinimide thioethers formed by maleimide-thiol conjugation. Ring-opening of conjugates prepared with commonly used maleimides were too slow to serve as prevention against thiol exchange. However, ring-opening rates are greatly accelerated by electron withdrawing N-substituents, and ring-opened products have half-lives of over two years. Thus, conjugates made with electron-withdrawing maleimides may be purposefully hydrolyzed to their ring-opened counterparts in vitro to ensure in vivo stability.