A series of 1-(aminoalkyl)- and 1-[(4-aryl-1-piperazinyl)alkyl]oxazolo[5,4-b]pyridin-2(1H)-one derivatives of oxazolo[5,4-b]pyridin-2(1H)-one, incorporating modifications to the length of the alkyl side chain and to the amino or 4-aryl-1-piperazinyl substituents, were tested for safety and analgesic efficacy in mice and rats. Some compounds with 4-(substituted or nonsubstituted phenyl)-1-piperazinyl substituents and a 3-4-carbon alkyl side chain had significantly greater analgesic activity than that of the oxazolo[4,5-b]pyridin-2(3H)-one analogs. To reduce the metabolic N-dealkylation of the piperazine observed in our previous work on oxazolo[4,5-b]-pyridin-2(3H)-ones, analogs of the most active compounds with steric hindrance on the alkyl side chain were prepared and tested. The compound with the maximal combination of safety and analgesic efficacy was 1-[[4-(4-fluorophenyl)-1-piperazinyl]propyl]oxazolo[5,4-b]pyridin- 2(1H)-one (compound 3b), with ED50 values of 5.6 mg/kg po (mouse, phenylquinone writhing test) and 0.5 mg/kg po (rat, acetic acid writhing test). Compound 3b is a potent, rapid-acting, non-opioid, nonantiinflammatory analgesic with low acute toxicity and sustained effect.