There is consistent evidence showing an interplay between psychological processes and immune function in health and disease processes.The present systematic review and meta-analysis aims to provide a concise overview of the effectiveness of stress-reducing psychological interventions on the activation of immune responses in both healthy subjects and patients.Included are 3 types of challenges: in vivo, in vitro, and psychophysiological. Such challenges are designed to mimic naturally occurring immune-related threats.A systematic literature search was conducted using PubMed, EMBASE, and PsychInfo, resulting in 75 eligible studies. The risk of bias was assessed with the Cochrane risk-of-bias tool. Across all studies, a small-to-medium effect size was found for the effects of psychological interventions on optimization of the immune function (g = 0.33; 95% CI 0.22-0.43). While the largest effects were found for in vivo immune-related challenges (g = 0.61; 95% CI 0.34-0.88; especially on studies that incorporated skin tests and wound healing), studies incorporating psychophysiological challenges and in vitro immune-related stimulations similarly suggest more optimal immune responses among those receiving stress-reducing interventions (g = 0.28; 95% CI 0.15-0.42).These findings showed substantial heterogeneity depending on the type of challenge, the study populations, and the intervention types. These data demonstrate support for the effectiveness of stress-reducing psychological interventions in improving immunity in studies that tested immune function by means of incorporating an in vivo,in vitro, or psychophysiological challenge. Future research should more consistently incorporate challenges into the study design to gather more insights in the mechanisms underlying the optimized immune function following a psychological intervention. This is also relevant for clinical practice, as psychological interventions can possibly supplement, or at least partially replace, current drug treatments in various somatic conditions to reduce side effects.