Twenty-six free-ranging North American bison (Bison bison) (22 adult bulls, one yearling male and three adult females) were immobilized using a combination of carfentanil and xylazine. For carfentanil the dose range (mean ± SD) was 1.8–5.0 μg/kg (2.4 ± 0.7 μg/kg) and for xylazine 0.004–0.125 mg/kg (0.07 ± 0.03 mg/kg). Induction time (mean ± SE) was 14.2 ± 2.9 min (median 8 min), while the total mean reversal time after administration of a narcotic antagonist was 9.0 ± 1.4 min (median 8 min). Only one animal that received the highest initial dose of carfentanil (2.5 mg) showed evidence of becoming “re-narcotized.” Five animals required two or more doses of carfentanil before becoming immobilized. Overall, small volumes of drug used (mean = 0.62 ml for carfentanil, 0.53 ml for xylazine) enabled the use of 1 to 2 ml darts, increasing both accuracy and impact safety. Darting success approached 100%.