Major burns elicit an acute inflammatory response including various inflammatory cytokines. Cytokines play mutual interacting roles in inflammatory diseases. There is little evidence of the clinical significance of the cytokine network in patients with major burns. This study aimed to investigate the clinical significance of the cytokine network in patients with major burn. This prospective observational study comprising 38 patients with major burns (total body surface area (%TBSA) ≥ 20%) and 12 healthy controls was conducted from April 2014 to December 2016. Blood samples were collected from patients at six points: day 1, day 2, days 3–5, 1 week, 2 weeks and 1 month after the burn injury. Inflammatory cytokines (IFN-α, IFN-γ, IL-1β, IL-6, IL-8, IL-12/IL-23p40, IL-17A, MCP-1, TNF-α) and anti-inflammatory cytokines (IL-4, IL-10) were measured. Twenty-eight-day mortality, %TBSA, prognostic burn index (PBI) and SOFA and APACHE II scores were evaluated. Hierarchical clustering analysis and network visualization showed one cluster and network, respectively. Both were formed by four cytokines including IL-6, IL-8, IL-10 and MCP-1 on days 1 and 2, suggesting the presence of a cytokine network in the early hospital phase. Each cytokine showed significant associations with the SOFA score within 5 days and 1 month after burn injury. Cox regression analysis highlighting days 1 and 2 showed significant correlation of IL-6, IL-8 and IL-10 with 28-day mortality. We showed a cytokine network and its relation with prognosis and injury severity on days 1 and 2 and suggest that this cytokine network may play a role in major burns.