This study introduces a radical-free approach for generating polyacrylamide (PAM) hydrogels with no toxic residues remaining in the networks. Acrylamide and bisacrylamide, which are neurotoxins, are not used during the hydrogel synthesis and only nontoxic side products are generated. This is achieved using a gentle carbodiimide-mediated crosslinking (CMCL) reaction that does not require complex initiation systems and is effective in the presence of oxygen. This overcomes some of the key limitations related to PAM hydrogel synthesis using free-radical routes and maintains the advantages of synthetic hydrogels over biopolymers. In addition, the CMCL reaction allows for accurate placement of functional groups, which controls hydrogel structure and performance including mechanical strength, swelling capacity, and hydrophobic balance. This flexibility is demonstrated through the synthesis and rheological characterization of a library of structurally diverse hydrogels as well as spherical hydrogels. PAM-based hydrogels are used extensively in a broad number of applications, and this study demonstrates the applicability of this method as a nontoxic and radical-free complementary alternative route that can generate structures analogous to those prepared using free-radical routes. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40416.