The prognosis of dengue remains a challenge in the early, objective triage of patients with dengue fever of differing severity. Circulating immuno-modulating proteins have brought new possibilities as prognostic markers of severe dengue (SD). This systematic review is devoted to understanding the potential utility of blood-based cytokines and chemokines as prognostication markers of SD based on the current literature. PubMed and Embase were searched. Of 794 candidate articles, 685 abstracts were screened against our exclusion/inclusion criteria and 25 (3.6 %) studies met the quality assessments. A total of 18 studies were retrospective observational and 2 were prospective cohort studies. Elevated IL-10, up to day 7 of fever onset, stood out as a candidate prognostic marker for SD using the 1997 and 2009 World Health Organization (WHO) case definitions. IFNγ was another potential prognostic marker of SD (1997 WHO case definition), but its levels varied between studies. Significant heterogeneity in methodologies and patient cohorts prevent ready application of IL-10 and IFNγ as prognostic markers to other dengue populations. Our results suggest that the current non-randomized studies are delivering inconsistent messages and higher-quality studies, with consistent methodologies and validation in independent patient cohorts, are needed to delineate confounding variables. Major gaps identified were full accounting and transparency of sampling days, dengue virus type, infection status and age group.