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Background: Primary immunodeficiencies (PIDs) in adults are mainly revealed by recurrent and/or severe bacterial infections. The objective of this study was to evaluate a systematic research strategy of PIDs in adults with unexplained bacterial infections, with a special focus on specific polysaccharide antibody deficiency (SPAD)., Methods: In this prospective multicenter study, inclusion criteria were recurrent benign upper and lower respiratory tract infections (RTIs) for at least two years (group 1), at least one upper or lower RTI requiring hospitalization (group 2), and/or at least one invasive infection documented with encapsulated bacteria (group 3). Main exclusion criteria were all local and general conditions that could explain infections. If no PID diagnosis was made, response to polysaccharide antigens was assessed using a pneumococcal polysaccharide vaccine., Results: From March 2015 to March 2020, 118 patients were included (37 males, median age of 41 years): 73, 17, and 28 in groups 1, 2, and 3, respectively. Forty-seven PIDs were diagnosed, giving an estimated frequency of 39.8% (95% confidence interval [CI] [30.4, 48.8]). SPAD was the most frequent diagnosis by far (n = 37/47, 78.7%), and was made in 23, 5, and 9 patients from groups 1 to 3, respectively. All SPAD patients received conjugate vaccines and, according to their infectious history, were on surveillance or treated with preventive antibiotics (n = 6) and/or with immunoglobulins replacement therapy (n = 10), the latter being dramatically efficient in all cases., Conclusions: Considering its high prevalence among adults with unexplained recurrent and/or severe bacterial infections, SPAD should be screened in those patients., Clinical Trials Registration: NCT02972281., Competing Interests: Potential conflicts of interest. S. S. reports travel grants from Shire, Sanofi-Genzyme, SOBI and Novartis; consulting fees from Novartis, Biocryst, and Takeda; outside the submitted work. O. L. R. reports interventions, expertise, or non-financial support unrelated to the submitted work from AstraZeneca, Boehringer Ingelheim, Chiesi, Correvio, GlaxoSmithKline, Lilly, Mayoli, MSD, Mylan, Novartis, Pfizer, Vertex, Vitalaire, and Zambon. G. L. reports interventions, expertise, or travel grants from LFB, Octapharma, Sanofi-Genzyme, GSK, AstraZeneca, Biotest, Takeda, CSL Behring, grants unrelated to this work and paid to Lille University Hospital from LFB, Octapharma, CSL Behring, Vitalaire, and The Binding Site; payment or honoraria from Octabpharma, Shire/Takeda, and Biotest; support for attending meetings and/or travel from CSL Behring and Bitoest. A. L. reports payment or honoraria of less than $<500 for education events from GSK; and support for meetings and travel, $<1000, from GSK. L. T. reports consulting fees paid to author from GRIFOLS. D. L. reports grants or contracts from CSL Behring and Servier, unrelated to this work; consulting fees paid to author from Takeda, CSL Behring, and Octapharma; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biocryst and Takeda; support for attending meetings and/or travel from Biocryst; participation on a Data Safety Monitoring Board or Advisory Board from Takeda and Biocryst; and receipt of equipment, materials, drugs, medical writing, gifts or other services from Mallinckrodt. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)