The muscle relaxant activities of orphenadrine (Norflex) and diazepam (Valium) were compared in several animal models. In mice, tonic extensor seizures evoked by electroshock or pentylenetetrazol were inhibited by both agents. The protective index (ataxic dose divided by protective dose) was greater than 1 for orphenadrine, whereas for diazepam it was greater than 1 only in the case of the pentylenetetrazol-induced seizures. In strychnine-treated mice, diazepam protected against deaths following tonic extensor seizures, but orphenadrine did not. The protective index for diazepam, however, was less than 1. In cats, orphenadrine and diazepam both were capable of blocking decerebrate ridigity, but not in all animals. The protective index for orphenadrine in animals in which it was active, was greater than 1, while that for diazepam, when it was active, was less than 1. Orphenadrine and diazepam were tested in rabbits in the sciatic nerve-gastrocnemius muscle preparation. Neither drug directly affected nerve muscle stimulation. It would appear that both agents are acting via the central nervous system when they suppress hypertonic skeletal muscle activity, but only orphenadrine exhibits protective indices consistently greater than 1.