This study investigates the biological parameters and genetic factors associated with hereditary angioedema (HAE) with normal C1 inhibitor (HAE-nC1-INH) and carboxypeptidase N (CPN) deficiency in four unrelated families. Patients presented with recurrent angioedema and urticaria, often triggered by specific triggers such as stress or cold. Plasma CPN activity was significantly lower in symptomatic patients compared to healthy controls, ranging from 30% to 50% of the median value. Genetic analysis identified three variants in the *CPN1* gene: c.533G>A, c.582A>G, and c.734C>T. These variants segregated with HAE-nC1-INH symptoms in affected family members. The variants were predicted to be deleterious or disease-causing based on various bioinformatics tools. The findings suggest that CPN deficiency contributes to bradykinin and anaphylatoxin accumulation, leading to synergistic effects in angioedema and urticarial symptoms. This study highlights the importance of genetic testing and clinical evaluation in diagnosing HAE-nC1-INH with CPN deficiency.This study investigates the biological parameters and genetic factors associated with hereditary angioedema (HAE) with normal C1 inhibitor (HAE-nC1-INH) and carboxypeptidase N (CPN) deficiency in four unrelated families. Patients presented with recurrent angioedema and urticaria, often triggered by specific triggers such as stress or cold. Plasma CPN activity was significantly lower in symptomatic patients compared to healthy controls, ranging from 30% to 50% of the median value. Genetic analysis identified three variants in the *CPN1* gene: c.533G>A, c.582A>G, and c.734C>T. These variants segregated with HAE-nC1-INH symptoms in affected family members. The variants were predicted to be deleterious or disease-causing based on various bioinformatics tools. The findings suggest that CPN deficiency contributes to bradykinin and anaphylatoxin accumulation, leading to synergistic effects in angioedema and urticarial symptoms. This study highlights the importance of genetic testing and clinical evaluation in diagnosing HAE-nC1-INH with CPN deficiency.