['Many outer multidomain proteins play fundamental virulent roles in an allele-dependent manner. We aimed to investigate the influence of the outer SP1992 protein, here renamed DiiA (Dimorphic invasion-involved A), in pneumococcal disease.', 'The presence and type of diiA allele was screened by PCR in 560 clinical isolates. Isogenic mutants carrying progressive diiA deletions were constructed and checked in mouse models of infection. DiiA binding to human molecules was carried out by surface plasmon resonance.', 'The diiA gene is exclusive of Streptococcus pneumoniae and included in the core genome. DiiA variants contain one or two imperfect repeats (R1 and R2), an unstructured region and a cell-wall anchor domain. Clonal complexes carrying both repeats were associated with invasive disease, while those carrying R2 preferentially caused non-invasive syndromes in patients with underlying risk factors. Mutants lacking both repeats were less efficient in nasopharyngeal colonization and dissemination from lungs. Moreover, the ΔdiiA defective strain suffered a severe impairment in bacterial proliferation in blood. Purified DiiA bound to collagen and lactoferrin with high affinity.'] Is diiA a novel dimorphic cell wall protein of Streptococcus pneumoniae involved in invasive disease?