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BackgroundAn outbreak of diphtheria, declared in Yemen in October 2017, is still ongoing. Methods. Probable cases were recorded through an electronic diseases early warning system. Microbiological culture, genomic sequencing, antimicrobial susceptibility and toxin production testing were performed.MethodsProbable cases were recorded through an electronic diseases early warning system. Microbiological culture, genomic sequencing, antimicrobial susceptibility and toxin production testing were performed.FindingsThe Yemen diphtheria outbreak developed in three epidemic waves, which affected nearly all governorates (provinces) of Yemen, with 5701 probable cases and 330 deaths (October 2017 - April 2020). The median age of patients was 12 years (range, 0.17-80). Virtually all outbreak isolates (40 of 43 tested ones) produced the diphtheria toxin. We observed low level of antimicrobial resistance to penicillin. We identified six separate Corynebacterium diphtheriae phylogenetic sublineages, three of which are genetically related to isolates from Saudi Arabia and Somalia. The predominant sublineage was resistant to trimethoprim and was associated with unique genomic features, more frequent neck swelling (p=0.002) and a younger age of patients (p=0.06). Its evolutionary rate was estimated at 1.67 × 10−6 substitutions per site year-1, placing its most recent common ancestor in 2015, and indicating silent circulation of C. diphtheriae in Yemen earlier than outbreak declaration.InterpretationWe disclose clinical, epidemiological and microbiological characteristics of one of the largest contemporary diphtheria outbreaks and demonstrate clinically relevant heterogeneity of C. diphtheriae isolates, underlining the need for laboratory capacity and real-time microbiological analyses to inform prevention, treatment and control of diphtheria.FundingThis work was supported by institutional funding from the National Centre of the Public Health Laboratories (Sanaa, Yemen) and Institut Pasteur (Paris, France) and by the French Government Investissement d ‘Avenir Program.