AbstractDeficiency of mannose‐binding lectin (MBL), a recognition molecule of the lectin pathway of complement, is associated with increased susceptibility to infections. The high frequency of MBL deficiency suggests that defective MBL‐mediated innate immunity can be compensated by alternative defense strategies. To examine this hypothesis, complement activation by MBL‐binding ligands was studied. The results show that the prototypic MBL ligand mannan can induce complement activation via both the lectin pathway and the classical pathway. Furthermore, antibody binding to mannan restored complement activation in MBL‐deficient serum in a C1q‐dependent manner. Cooperation between the classical pathway and the lectin pathway was also observed for complement activation by protein 60 from Listeria monocytogenes. MBL pathway analysis at the levels of C4 and C5b–9 in the presence of classical pathway inhibition revealed a large variation of MBL pathway activity, depending on mbl2 gene polymorphisms. MBL pathway dysfunction in variant allele carriers is associated with reduced MBL ligand binding and a relative increase of low‐molecular‐mass MBL. These findings indicate that antibody‐mediated classical pathway activation can compensate for impaired target opsonization via the MBL pathway in MBL‐deficient individuals, and imply that MBL deficiency may become clinically relevant in absence of a concomitant adaptive immune response.