The in vivo reduction kinetics of twenty different nitroxide compounds in mice has been investigated by using an electron paramagnetic resonance (EPR) spectrometer, equipped with an S-band loop-gap resonator, operating at 3.5 GHz. The diameter of the resonator (4 mm) fits well the tip of the mouse tail, thus allowing the direct detection of in vivo free radicals in the blood circulation. After intravenous injection, the nitroxide signal in the circulation of the mouse tail was followed with time; no anesthetic agent was used. For the pyrrolidine nitroxides (five-member rings) with different functional groups, the t1/2 values followed the order: = O > COO- > OH > CONH2 approximately CH2NH2 > NH2. A different trend was obtained for the piperidine nitroxides (six-member rings): COO- > CH2NH2 > OH approximately NH2 > CONH2 > = O. The most striking observation was that while the t1/2 value of the cabonyl pyrrolidine is the longest among all the nitroxides tested for this property, that of the carbonyl piperidine is the shortest. Comparison of the in vivo decay kinetics of six pairs of pyrrolidine nitroxides and piperidine nitroxides with same functional groups showed that the t1/2 values of the former are 2 to 28 times longer than the latter. It is concluded here that the pyrrolidine nitroxides are more resistant to cellular metabolism in vivo when compared to the piperidine nitroxides.