Handling stress and capture myopathy are important consequences of intensively managing wildlife species. Over the last 15 yr, the use of long-acting neuroleptic (LAN) drugs in wildlife has increased, and these drugs have become a valuable tool for decreasing capture and handling stress in many species. At this time, reports on the use of these drugs in North American species are limited. The major objective of this study was to evaluate the use of the LAN, zuclopenthixol acetate (Clopixol-Acuphase®), to decrease both quantifiable and subjective measurements of stress and activity in wild wapiti (Cervus elaphus, North American elk). This blinded, randomized study took place in February 1999 in Manitoba (Canada) and involved 11 animals receiving the drug and 12 animals acting as controls. At 24 hr after drug administration, there were measurable and significant decreases in the stress and activity of treated animals versus controls during handling. Treated animals had significantly lower mean body temperatures (39.0 versus 40.6 C), less hemoconcentration (mean packed cell volume 0.42 versus 0.49, mean hemoglobin 159.09 versus 181.75 g/L, mean total protein 65.0 versus 70.25 g/L), lower mean serum cortisol (97.91 versus 139.50 mmol/L), lower mean blood lactate (3.39 versus 5.98 mmol/L), and were less metabolically acidotic (mean pH_v 7.45 versus 7.34, mean bicarbonate 29.36 versus 24.25 mmol/L, mean base excess 5.64 versus −0.83 mmol/L). Only control animals had evidence of muscle damage based on serum biochemistry (creatine phosphate values of two animals of 42,080 and 25,887 U/L). No animals developed clinical capture myopathy, and no animals died. Measurable effects of this drug were still apparent at 72 hr post-administration. The results of this study support the use of Clopixol-Acuphase® in wapiti as a means to decrease handling stress and activity.