This study addresses the colloidal stability of polymer-coated core/shell CdSe/Cd x Zn 1−x S quantum dots (QDs) in the presence of L-glutathione (GSH) under neutral conditions by means of photoluminescence (PL) and absorption spectroscopy. A reversible addition−fragmentation chain-transfer-mediated synthesis was employed to produce co-polymer ligands with different molecular weights in block and random sequences. Poly(ethylene glycol) sidechains were incorporated on a methacrylate backbone for solubility in phosphate-buffered saline. Imidazole-bearing histamine sidechains were installed postsynthetically to facilitate binding to the QD surface. Introduction of L-glutathione, an endogenous monothiol, to aqueous solutions of the polymer-coated QDs led to an increase in PL quantum yield, indicating an interaction between the QD and glutathione. The PL change was greatly diminished for block co-polymers versus random co-polymers of similar molecular weight and composition. Additionally, higher ligand populations were found upon initial purification of block co-polymer-coated QDs versus the random co-polymers. We demonstrate that glutathione does not significantly displace the polymer ligands from the QD surface, suggesting that PL changes are driven primarily through ligand association. The block copolymers are more resistant to glutathione association, and indeed stronger binders, than the randomly ordered co-polymers, with higher-molecular-weight contributing to improved stability in both cases. To the best of our knowledge, this is the first study to directly compare the relative stability of block and random polymeric imidazole ligands and should aid in developing more stable ligand-exchanged QDs for bioimaging and biosensing, especially for in vivo and intracellular applications.