Aims: Leptospirosis is a widespread zoonosis with more than 1 million cases of human contaminations estimated annually. The disease is polymorphic with asymptomatic forms or clinical manifestations ranging from mild to severe forms possibly leading to death. Using a comparative study between susceptible (hamster) and resistant (OF1 mouse) animals infected with virulent leptospires, we previously showed that the anti-inflammatory interleukin-10 (IL-10), although upregulated in both animals, was rapidly and massively overexpressed in mice. We aimed at better understanding the role of IL-10 in the disease pathophysiology, and its possible involvement in the resistance of mouse to leptospirosis. Methods: Using anti-IL-10 antibody (Ab) as a pre-infection treatment, we studied the effect of IL-10 neutralization on the resistance of the OF1 mice infected with virulent leptospires (Leptospira interrogans serovar Icterohaemorrhagiae). Growth variation was evaluated as a clinical sign after infection. The presence of leptospires was investigated in kidneys at D7; IL-1β and TNF-α gene expression in blood was assessed at D3 using RT-qPCR techniques. Results: While either infection with virulent leptospires or Ab treatment did not affect the growth curve of mice, IL-10 neutralization significantly influenced the mouse growth during the early days (D1 and D2) postinfection suggesting a susceptibility of animals. Leptospires were detected in the kidneys of 5/7 infected mice (71.5%) whereas only 2/8 of Ab-injected animals (25%) were found positive for renal carriage. Quantification of cytokine gene expression did not show regulation of neither IL-1β nor TNF-α in blood of leptospiremic mice at D3. However, both cytokines were significantly up-regulated in infected animals pre-treated with anti-IL-10 ab. Conclusion: Results suggest that IL-10 neutralization might impact on the resistance of mouse to Leptospira infection, possibly related to an up-regulation of IL-1β and TNF-α, illustrating the possible key role of this cytokine in the immune response to leptospirosis.