Effective adjustment of the stress systems to repeated stress is regarded as an adaptive response of the organism facing environmental threats. Given the intertwined relationship between the stress systems and the inflammatory system, it could be expected that inflammatory processes should adapt to repeated stress as well. However, only little is known about adaptational processes of the different components of the immune system in response to repeated stress, and how these might be related to adaptational processes of the hypothalamus-pituitary-adrenal (HPA) axis. We here examined N=22 healthy participants (mean age 23years, 50% female) and exposed them to a standardized laboratory stressor twice, 24h apart. Plasma interleukin 6 (IL-6), salivary cortisol and psychometric parameters were assessed repeatedly up to 120min post stress. Results revealed a significant day by time interaction for cortisol (F=5.06; p=0.013) and IL-6 (F=4.42; p=0.041), indicating habituation of HPA axis and sensitization of inflammatory stress responses. Cortisol habituation and inflammatory sensitization were inversely related when controlling for sex (r=-0.44; p=0.044). Explorative analyses revealed significant associations between the IL-6 response on the second exposure with perceived stress (r=0.58; p=0.004), vital exhaustion (r=0.57; p=0.009), depression (r=0.47; p=0.026) and purpose in life (r=-0.50; p=0.04). These findings may help to increase understanding of the still only rudimentary understood interplay of adaptational processes of endocrine and immune responses to repeated stress and might indicate a link between inflammatory disinhibition and psychological indicators of well-being.