The autonomic nervous system interacts with the immune system via the inflammatory response. Heart rate variability (HRV), a marker of autonomic activity, is associated with inflammation, and nosocomial infections/sepsis, and has clinical implications for the monitoring of at-risk patients. Due to the vagal tone's influence on anti-inflammatory immune response, this association may predominately be reflected by vagally-mediated HRV indices. However, HRV's predictive significance on inflammation/infection remains unclear. 843 studies examining the associations/prognostic value of HRV indices on inflammation, and nosocomial infection/sepsis were screened in this systematic review. According to inclusion and exclusion criteria, 68 associative studies and 14 prediction studies were included. HRV and pro-inflammatory state were consistently associated in healthy subjects and patient groups. Pro-inflammatory state was related to reduced total power HRV including vagally- and non-vagally-mediated HRV indices. Similar, compared to controls, HRV reductions were observed during nosocomial infections/sepsis. Only limited evidence supports the predictive value of HRV in the development of nosocomial infections/sepsis. Reduced very low frequency power HRV showed the highest predictive value in adults, even with different clinical conditions. In neonates, an increased heart rate characteristic score, combining reduced total power HRV, decreased complexity, and vagally-dominated asymmetry, predicted sepsis. Pro-inflammatory state is related to an overall reduction in HRV rather than a singular reduction in vagally-mediated HRV indices, reflecting the complex autonomic-regulatory changes occurring during inflammation. The potential benefit of using continuous HRV monitoring for detecting nosocomial infection-related states, and the implications for clinical outcome, need further clarification. •The autonomic nervous system controls inflammation via cholinergic pathways.•Heart rate variability (HRV) is a cardiac biomarker of autonomic activity.•HRV is reduced during inflammation.•Selective changes of parasympathetic component were not identified.•HRV monitoring in predicting nosocomial infections/sepsis needs further clarification.