Spinal neostigmine causes analgesia in animals and humans and abolishes hypotension from spinal bupivacaine in rats. Since drug distribution and action can vary with the size of the spinal cord, we tested the effects of the maximum tolerated dose of spinal neostigmine alone and with bupivacaine in conscious sheep. Neostigmine alone increased arterial blood pressure by 10%, with a statistically significant increase beginning 30 min after injection. Compared with spinal bupivacaine alone, addition of neostigmine resulted in hypotension of slower onset (15 vs 5 min), shorter duration (45 vs 105 min), and smaller magnitude (-18% +/- 3% vs -37% +/- 6%). Addition of neostigmine did not affect height of sensory block from spinal bupivacaine. These data agree with preliminary clinical reports that spinal neostigmine diminishes, but does not abolish, hypotension from spinal bupivacaine in humans.