<b><i>Background:</i></b> Cytokines have been shown to be involved in traumatic brain injury (TBI). We investigated the independent association between serum levels of IL-10 and TNF-α and hospital mortality of patients with severe TBI. <b><i>Methods:</i></b> Serum IL-10 and TNF-α levels were determined after a median period (interquartile range (IQ) 25–75) of 10 h (IQ 5–18) after severe TBI in 93 consecutive patients and in randomly selected patients with mild (n = 18) and moderate (n = 16) TBI. In patients with severe TBI, additional blood samples were analyzed 30 h (IQ 22–37) and 68 h (IQ 55–78) after TBI. Age, gender, computed tomography findings, Glasgow Coma Scale score (GCS) and pupil reactions at admission, associated trauma and hospital mortality were collected. <b><i>Results:</i></b> Elevated serum levels of IL-10, but not TNF-α, correlated significantly with GCS severity (R² coefficient, p < 0.0001) and were found to be associated with hospital mortality in patients with severe TBI. Elevated IL-10 remained associated with mortality (p = 0.01) in a subset of patients with isolated severe TBI (n = 74). Multiple logistic regression analysis showed that higher IL-10 levels (>90 pg/ml) at 10 or 30 h after TBI were 6 times (odds ratio (OR) 6.2, 95% confidence interval (CI) 1.2–25.1, p = 0.03) and 5 times (OR 5.4, 95% CI 1.2–25.1, p = 0.03), respectively, more frequently associated with hospital mortality than lower levels (<50 pg/ml), independently of age, GCS as well as pupil reactions at admission and associated trauma. <b><i>Conclusions:</i></b> Serum IL-10 levels may be a useful marker for severe TBI prognosis.