Background Adiponectin, an adipocyte-secreted protein-hormone with inflammatory properties, has a potentially important role in the development and progression of asthma. Unravelling whether adiponectin is a causal risk factor for asthma is an important issue to clarify as adiponectin could be a potential novel drug target for the treatment of asthma. Objective We tested the hypothesis that plasma adiponectin is associated observationally and causally (using genetic variants as instrumental variables) with risk of asthma. Methods In the Copenhagen General Population Study, we did an observational analysis in 28 845 individuals (2278 asthma cases) with plasma adiponectin measurements, and a genetic one-sample Mendelian randomisation analysis in 94 868 individuals (7128 asthma cases) with 4 genetic variants. Furthermore, in the UK Biobank, we did a genetic two-sample Mendelian randomisation analysis in 462 933 individuals (53 598 asthma cases) with 12 genetic variants. Lastly, we meta-analysed the genetic findings. Results While a 1 unit log-transformed higher plasma adiponectin in the Copenhagen General Population Study was associated with an observational OR of 1.65 (95% CI 1.29 to 2.08) for asthma, the corresponding genetic causal OR was 1.03 (95% CI 0.75 to 1.42). The genetic causal OR for asthma in the UK Biobank was 1.00 (95% CI 0.99 to 1.00). Lastly, genetic meta-analysis confirmed lack of association between genetically high plasma adiponectin and causal OR for asthma. Conclusion Observationally, high plasma adiponectin is associated with increased risk of asthma; however, genetic evidence could not support a causal association between plasma adiponectin and asthma.