The present study was conducted to evaluate the prognostic significance of selected inflammatory markers for prediction of clinical outcomes of traumatic reticuloperitonitis (TRP) in water buffalo (Bubalus bubalis). Acute local TRP was initially diagnosed in 32 buffalo by clinical examination and confirmed by ultrasonography (USG), laparo-rumenotomy and/or necropsy findings in non-surviving cases. Ten clinically healthy buffalo were randomly selected and served as controls. Blood was drawn from all examined buffalo to measure the respective levels of tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-6, IL-10 interferon gamma (INF)-γ, serum amyloid A (SAA), haptoglobin (Hp), fibrinogen (Fb), C-reactive protein (CRP) and serum sialic acid (SSA). Clinically, the heart rates, but neither respiratory rate nor rectal temperature, were significantly higher in non-survivors compared with survivors (P < 0.05). In addition, the non-surviving buffalo were more likely to have anorexia and weakness compared with survivors. However, rumen stasis, recurrent ruminal tympany, lacrimation, lordosis, bruxism, and decreased milk production were commonly observed in all diseased animals. Biochemically, TNF-α, IL-1β, IL-6, IL-10, SAA, Hp, Fb, CRP, and SSA levels were significantly higher in diseased buffalo compared with controls, and were higher in non-survivors than survivors (P < 0.05). The data herein indicate an ongoing cascade of systemic inflammatory responses in buffalo with TRP with concomitant compensatory anti-inflammatory reactions and the overall degree of cytokine network disruption may be an important prognostic indicator. Medical strategies to modulate inflammation must take into account the complex of cytokine biology in buffalo with TRP.