Aleutian disease (AD) is a devastating infectious disease in American mink (Neogale vison) industry caused by Aleutian mink disease virus (AMDV). Two crucial steps toward controlling infectious diseases in farm animals are: (i) assessment of the infection risk factors to minimize the likelihood of infection and (ii) selection of animals with superior immune responses against pathogens to build tolerant farms. This study aimed to investigate AD risk factors and evaluate a novel “ImmunAD” approach for genetic improvement of AD tolerance. Phenotypic records and pedigree information of 1,366 and 24,633 animals were included in this study. The risk of animal’s age, sex, color type, and year of sampling on AMDV infection was assessed using a logistic regression model and counter immune-electrophoresis (CIEP) test results. ImmunAD phenotype was calculated based on AMDVG enzyme-linked immunosorbent assay (ELISA) and CIEP test results, and breeding values for ImmunAD were estimated using an animal model. Animals were classified into high-coordinated (HCIR), average-coordinated (ACIR), and low-coordinated immune responders (LCIR) using ImmunAD’s breeding values, and the impact of selection of HCIR on live grade of pelt quality (PQ), harvest weight (HW), and harvest length (HL) breeding values were evaluated. Age of > 1 year, male sex, and year of sampling were identified as significant risk factors of AD (p < 0.05). A moderate-to-high heritability (0.55±0.07) was estimated for ImmunAD, while a higher heritability was observed among the CIEP-positive animals (0.76±0.06). Significantly higher breeding values were observed for PQ and HL among HCIR than those for LCIR and ACIR (p < 0.05). Our findings indicate the critical role of male breeders in AD distribution within mink farms. Regular screening of AD in male breeders before pairing them with females during breeding seasons can help disease control. ImmunAD strategy can be applied to genetic improvement of AD tolerance, with favorable impacts on some growth and production traits. Higher genetic gains can be achieved in populations with higher AD seroprevalences.