Leptospirosis is a zoonotic disease caused by the pathogenic strains of Leptospira. Outbreaks of leptospirosis have been reported following water sports events and floods particularly in men. The symptoms range from mild acute febrile illness to severe form with multi organ failure. Severe leptospirosis increases the likelihood of mortality and may require medical interventions in the form of dialysis and/or mechanical ventilation. It is important to predict severe leptospirosis to optimize medical care since non-severe patients reported to progress to severe form during the immune phase of the illness. The exaggerated host immune response causing endothelial and organ damages was shown to be associated with disease severity and mortality. This review presents the association of immune and endothelial activation markers, biochemical and genetic markers with disease severity in leptospirosis.