This prospective study aimed to delineate the association between the serum levels of macrophage migration inhibitory factor (MIF) and the risks of early mortality in 112 patients who presented with clinically severe sepsis. Previous studies showed that elevated serum MIF levels on the first day are associated with an increased risk of 28-day mortality. Nonsurvivors may be the sickest population on arrival. Not all patients with severe sepsis follow the same clinical pathway, however, and the sequential change in MIF might be an important predictor of mortality. We hypothesized that, for septic patients, in addition to serum MIF levels on day 1, the percentage of change in MIF between days 1 and 2 after arriving in the emergency department predicts the probability of early mortality. Serum MIF levels were measured on days 1 (emergency department arrival) and 2 (24 h after arrival). Patients with a high percentage of increase between MIF levels on days 1 and 2 had higher 3-day (odds ratio, 1.8; 95% confidence interval, 1.2-2.6; P = 0.003) and 7-day mortalities (odds ratio, 1.4; 95% confidence interval, 1.0-1.9; P = 0.03) after adjusting for age and day-1 serum MIF levels. In conclusion, an increase in serum MIF from the first to second day of admission in patients with severe sepsis indicates a higher risk of early mortality; therefore, these patients need more aggressive therapeutic intervention.