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Background Drug-resistant tuberculosis (DR-TB) is undermining TB control in South Africa. However, there are hardly any data about the cost of treating DR-TB in high burden settings despite such information being quintessential for the rational planning and allocation of resources by policy-makers, and to inform future cost-effectiveness analyses. Methodology We analysed the comparative 2011 United States dollar ()costofdiagnosisandtreatmentofdrugsensitiveTB(DS-TB),MDR-TBandXDR-TB,basedonNationalSouthAfricanTBguidelines,fromtheperspectiveoftheNationalTBProgramusingpublishedclinicaloutcomedata.PrincipalFindingsAssumingadherencetonationalDR-TBmanagementguidelines,theperpatientcostofXDR-TBwas 26,392, four times greater than MDR-TB (6772),and103timesgreaterthandrug-sensitiveTB( 257). Despite DR-TB comprising only 2.2% of the case burden, it consumed∼ 32% of the total estimated 2011 national TB budget of US 218million.45%and25%oftheDR-TBcostswereattributedtoanti-TBdrugsandhospitalization,respectively.XDR-TBconsumed28%ofthetotalDR-TBdiagnosisandtreatmentcosts.Laboratorytestingandanti-TBdrugscomprisedthemajority(71%)ofMDR-TBcostswhilehospitalizationandanti-TBdrugcostscomprisedthemajority(92%)ofXDR-TBcosts.AdecentralizedXDR-TBtreatmentprogrammecouldpotentiallyreducecostsby 6930 (26%) per case and reduce the total amount spent on DR-TB by∼ 7%. Conclusion/Significance Although DR-TB forms a very small proportion of the total case burden it consumes a disproportionate and substantial amount of South Africa’s total annual TB budget. These data inform …