Objective To explore the causal relationship between the Collagen VI (COL6) family proteins COL6A1, A2, and A3 and bronchiectasis using the Mendelian randomization (MR) method.MethodsThe primary analysis was conducted using MR combined with summary-data-based Mendelian randomization (SMR) analysis. COL6 family proteins were used as exposure data, and bronchiectasis was used as outcome data. Cis-protein quantitative trait locus (cis-pQTL) data were extracted for analysis, and the results were meta-analyzed. Subsequently, COL6A3-cis-pQTL data from the UK Biobank plasma proteome study were used for further validation. Colocalization analysis was also performed to further explore the association between COL6 proteins and bronchiectasis.Results MR and SMR results revealed a negative causal relationship between COL6A3 and bronchiectasis (p-MRmeta = 0.005, OR = 0.30; p-SMRmeta = 0.004, OR = 0.26). The validation phase also confirmed the negative causal relationship between COL6A3 and bronchiectasis (p-MRmeta = 0.000007, OR = 0.27; p-SMRmeta = 0.0003, OR = 0.29). Colocalization analysis supported the presence of a shared causal variant (rs972974) between COL6A3 and bronchiectasis (PP.H4 = 0.967/0.876).Conclusion There is an inverse causal relationship between COL6A3 and bronchiectasis. Low expression of COL6A3 increases the risk of developing bronchiectasis, making COL6A3 a potential biomarker and therapeutic target for drug development in bronchiectasis.