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Diphtheria is a life-threatening respiratory tract infection that causes outbreaks in susceptible populations. Between April and May 2018, an outbreak of diphtheria occurred in the eThekwini district. A school-based outbreak vaccination response was initiated to target vulnerable children and adolescents. Contribution: This study adds to the limited data describing a school-based vaccination in an outbreak response and highlights successes and challenges. School-based outbreak vaccination response can rapidly increase vaccine coverage; however, additional community engagement may be required in vaccine-hesitant populations.