Because of their paramagnetic properties, nitroxides are potentially useful as contrast agents in magnetic resonance imaging (MRI). They are reduced in vivo to their corresponding hydroxylamines which are nonparamagnetic and have no contrast enhancing property. Nitroxides with high resistance to reduction would be advantageous as pharmaceutical contrast enhancing agents. We show that in the presence of ascorbic acid and in tissue homogenates, the reduction is faster for piperidine than for pyrrolidine nitroxides and for positively-charged than for negatively-charged derivatives. The data also suggest that nitroxide reduction in tissue homogenates is mainly due to sulfhydryl groups on proteins and that endogenous ascorbic acid plays a relatively minor role.