Digoxin causes false-positive ST depression during exercise stress testing, but it is unknown if digoxin produces ST depression during ambulatory electrocardiographic monitoring. Fifty healthy volunteers underwent both exercise stress testing and ambulatory electrocardiographic monitoring before and after 14 days of digoxin (0.25 mg/day) administration. Significant ST depression was defined as greater than or equal to 1 mm of horizontal or downsloping ST depression 80 ms after the J point lasting for greater than or equal to 60 seconds. During therapy, 13 subjects (26%) had at least 1 episode of ST depression and 5 subjects (10%) had multiple episodes of ST depression detected by ambulatory monitoring. Ten subjects (20%) had ST depression that occurred during exercise that was detected by both stress test and ambulatory monitoring. Three subjects (6%) had ST depression that was detected on the ambulatory recording only at times other than during the stress test. Stratification of demographic and clinical variables did not predict digoxin-induced ST depression. Thus, digoxin causes false-positive ST depression detected by ambulatory monitoring. The incidence is similar to that observed during stress testing, but also occurs at heart rates lower than that achieved during stress tests. Ambulatory electrocardiographic monitoring will be less useful in the noninvasive assessment of coronary artery disease in patients receiving digoxin.