<p>Recent reports confirm that cystic fibrosis (CF) is a global disease. In Asian populations, both the spectrum of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and the clinical course differ from those observed in Western populations. Although the recognition of CF is increasing in South Asia, comprehensive data from Southeast Asian countries remain sparse. The underdiagnosis of CF in Southeast Asia is attributed to limited awareness among healthcare professionals and restricted access to sweat chloride testing. Until 2021, CF had not been documented in the indigenous population of Vietnam. This study presents the first three confirmed cases of CF in native Vietnamese individuals. Additionally, a literature review of CF cases reported across Southeast Asia was conducted to provide insights into its prevalence and variations in CFTR mutation profiles within the region. A total of 50 cases were identified, distributed across Malaysia (30 cases), Thailand (8), the Philippines (6), Vietnam (5), and Indonesia (1), revealing a mutation spectrum distinct from that observed in Caucasian populations. The most common mutations included p.Phe508del and p.Ile1295PhefsX32, each found in 11.5% of cases. These findings highlight the need for increased clinical awareness, expanded access to sweat chloride testing, and the establishment of CF centers and regional CF registries to better understand and manage CF in Southeast Asia.</p>