A number of evidence showed an emerging role of leptin on immune system, involving inflammation, and innate and adaptive immunity. Few observational studies have evaluated the relationship between leptin and immunity, albeit with low statistical power and methodological differences. Therefore, the aim of this study was to evaluate the potential role of leptin on the immunity, expressed as white blood cells (WBC)—and its subpopulations, by comprehensive multivariate models in a sample of adult men. A cross-sectional evaluation of a general population comprised 939 subjects participating in the Olivetti Heart Study, with available leptin levels and WBC—and its subpopulations. WBC were significantly and positively associated with leptin, C-reactive protein and HOMA index (p< 0.05), but not with age and anthropometric indices (p> 0.05). The multivariate analysis confirmed the association between leptin and WBC, after accounting for main confounders (p< 0.05). Additional analysis on WBC subpopulations showed a positive and significant correlation between leptin and lymphocytes, monocytes and eosinophils (p< 0.05), but not with neutrophils and basophils (p> 0.05). After stratification by body weight, the positive and significant association between leptin and WBC—and its subpopulations—was found in excess body weight participants. The results of this study indicate a direct relationship between leptin levels and WBC—and its subpopulations—in excess body weight participants. These results support the hypothesis that leptin has modulatory functions on immunity and role in the pathophysiology of immune-related diseases, in particular in those associated with excess body weight.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11739-023-03313-9.