A decrease in heart rate variability (HRV) can indicate increased sympathetic nervous system activity and possibly increased norepinephrine levels. In this randomized, placebo- and escitalopram (ESC)-controlled, subject-blind, 2-period, crossover study, 26 healthy subjects 50 to 65 years old received duloxetine (DLX) 60 mg once daily or ESC 20 mg once daily for 11 days, each in sequential study periods separated by a 10-day or more washout period. Continuous electrocardiogram recordings were obtained by Holter monitoring (baseline, day 9, and day 10 of treatment). Duloxetine and ESC did not produce any clinically significant effects on standard measures of HRV, which included SD of normal R-R intervals and the root mean square difference among successive R-R normal intervals index values, mean change in SD of normal R-R intervals, and frequency domain analysis. However, treatment with DLX was associated with significantly less change from baseline in total beats per 24 hours than ESC, which was an unexpected finding compared with previous observations in which vital signs were measured at a specific time point while awake. In conclusion, in healthy adults exposed to DLX or ESC, no clinically significant effects on HRV were observed.