Background: Leprosy is an infectious disease that remains hyperendemic in several Brazilian regions. Patient contacts face a higher risk for infection and illness, which can subsequently contribute to the persistence of the disease. Objective: This study investigates the risk factors associated with anti-phenolic glycolipid-I (anti-PGL-I) seropositivity and leprosy development among contacts of leprosy patients in a highly endemic region. Methods: A cohort of 629 contacts from the Almenara microregion, Minas Gerais, Brazil, was followed from 1998 to 2018. Our research group assessed risk factors, including sociodemographic determinants, bacillus exposure, and genetic susceptibility. Findings: Analysis revealed that living with a multibacillary (MB) leprosy patient [odds ratio (OR): 3.01, 95% confidence interval (CI): 1.02-8.86] and with a patient with grade II disabilities (OR: 4.43, 95% CI: 1.08-18.1) significantly increased the likelihood of anti-PGL-I seropositivity among asymptomatic contacts. Risk factors for leprosy included living with a patient in a shared residence (OR: 2.84, 95% CI: 1.21-6.67) and blood relation to the patient (OR: 2.56, 95% CI: 1.18-5.54). Notably, 98% of contacts who developed leprosy had lived with more than one patient. Main Conclusions: Clinical characteristics of index patients play a critical role in infection risk among contacts. Leprosy progression appears to depend on genetic susceptibility, type of contact, and extent of bacillus exposure.