Abstract The liver produces various ketone bodies (KBs) including 3-Hydroxybutyrate (3-OHB), acetoacetate (AcAc), and acetone, with 3-OHB being the major component. Previous studies have shown that KBs protect against respiratory diseases; however, there is no evidence of a genetic link. To avoid biases existing in traditional observational studies, a two-sample Mendelian randomization (MR) analysis was carried out to investigate genetic causation and novel therapeutic uses for KBs. This study used databases from genome-wide association studies (GWAS) and single nucleotide polymorphisms as instrumental variables for KBs from a recently published metabonomics study (n = 121,584) and respiratory diseases [lung cancer, n = 85,716; asthma, n = 127,669; chronic bronchitis, n = 450,422; chronic obstructive pulmonary disease (COPD), n = 468,475; FEV1/FVC