Abstract: The effects of digoxin on pulmonary vascular resistance (PVR) were evaluated in 13 normoxemic (N) newborn lambs (0-3 days of age) with normal PVR and in 4 of the 13 with hypoxic (H) induced increase in PVR. Lambs were anesthetized with chloralose and instrumented to enable continuous measurement of cardiac output (CO), pulmonary arterial pressure (PAP), left atrial pressure (LAP) and PVR. Digoxin was injected into a central venous catheter in doses ranging from 10-20 μg/kg. The mean (± SD) increase in PVR was 22.3% (± 21.4) in the N lambs (p< 0.001) and only 2% (± 8.5) in the H lambs (NS). The mean duration of the response was 199 sec (± 180). Since the LAP was unchanged, CO increased 7.2% (± 14) in the N lambs and 2.5% (± 6.9) in the H lambs, and the PAP increased 23.1% (± 16.2) in the N lambs and 3.9% (± 2.1) in the H lambs, the change in PVR appears to be due to a direct pulmonary vasoconstrictive response to digoxin. The blunted response in H lambs may have occurred because they were already maximally constricted or because digoxin and H induced vasoconstriction share a common mechanism such as electromechanical coupling with inhibition of calcium influx. Attempts to confirm the latter mechanism, using verapamil, were unsuccessful because even small doses proved lethal to lambs. The transient increase in PVR produced by digoxin may actually be beneficial to infants with patent ductus arteriosus and L→R shunting but could further compound existing pulmonary hypertension in other sick infants. A cautious approach to digitalization of newborns is warranted.