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Complement C3 plays a role in asthma development and severity. We tested the hypothesis that high plasma complement C3 concentration is associated with high risks of asthma hospitalisation and exacerbation.We prospectively assessed the risk of asthma hospitalisation in 101 029 individuals from the Copenhagen General Population Study with baseline measurements of plasma complement C3, and genotyped for rs1065489, rs429608 and rs448260 determining levels of complement C3. Risk of asthma exacerbation was further assessed in 2248 individuals with allergic asthma.The multivariable adjusted hazard ratio of asthma hospitalisation was 1.23 (95% CI 1.04-1.45) for individuals in the highest tertile (>1.19 g·L -1 ) of plasma complement C3 compared with those in the lowest tertile (<1.03 g·L -1 ). The C3 rs448260 genotype was associated with risk of asthma hospitalisation with an observed hazard ratio of 1.17 (95% CI 1.06-1.28) for the CC genotype compared with the AA genotype. High plasma complement C3 was associated with high levels of blood eosinophils and IgE (p for trends ≤6×10 -9 ), but only the SKIV2L rs429608 genotype was positively associated with blood eosinophil count (p=3×10 -4 ) and IgE level (p=3×10 -4 ). In allergic asthma, the multivariable adjusted incidence rate ratio for risk of exacerbation was 1.69 (95% CI 1.06-2.72) for individuals in the highest plasma complement C3 tertile (>1.24 g·L -1 ) versus the lowest (<1.06 g·L -1 ).In conclusion, a high concentration of plasma complement C3 was associated with a high risk of asthma hospitalisation in the general population and with a high risk of asthma exacerbation in individuals with allergic asthma. Our findings support a causal role of the complement system in asthma severity., Competing Interests: Conflict of interest: S. Vedel-Krogh has nothing to disclose. Conflict of interest: K.L. Rasmussen has nothing to disclose. Conflict of interest: B.G. Nordestgaard has nothing to disclose. Conflict of interest: S.F. Nielsen has nothing to disclose., (Copyright ©ERS 2021.)