Objective: The study sought to measure the effects of caffeinated and decaffeinated coffee on affective mood, sleep, and health-related quality of life (HRQL). Methods: Forty-nine healthy participants between the ages of 18 and 45 took part in a randomized, doubleblind, longitudinal study with decaffeinated coffee as the control. The participants began with a 5-day washout period, followed by a 5-day treatment phase, and concluded with a 5-day washout phase. Data were analyzed with repeated-measures analysis of covariance and ordinary least-squares mediational analysis. Results: The caffeinated coffee treatment group showed significant direct effects on sleep, anxiety, and stress-based domains of HRQL. In addition, mediational analysis showed that the more global domains of HRQL were affected indirectly through reduced sleep quality/quantity and through increases in anxiety. No significant changes were noted in the decaffeinated treatment group. Conclusions: Given the strong effect of caffeine on sleep and anxiety, as well as the indirect effect on HRQL in this study, it might be beneficial for individuals with stress responsive illnesses to refrain from high doses of caffeine. Further studies should examine the effects of caffeine in individuals with various stress-related illnesses. The results of caffeine on depression are contrary to previous studies, and further evaluations should examine variations of effects based on dosages and different populations (major depression diagnoses as well as healthy populations).