To explore the process, major players and procedural success factors for recent public sector TB regimen changes, we conducted 166 interviews of country stakeholders in 21 of the 22 TB high-burden countries (HBCs).Stakeholders described 40 distinct regimen changes for drug-susceptible TB. Once countries committed to considering a change, the average timing was ∼1 year for decision-making and ∼2 years for roll-out. Stakeholders more often cited concerns that were program-based (e.g., logistics and cost) rather than patient-focused (e.g., side effects), and patient representatives were seldom part of decision making. Decision-making bodies in higher-income HBCs had more formalized procedures and fewer international participants. Pilot studies focused on logistics were more common than effectiveness studies, and the evidence base was often felt to be insufficient. Once implementation started, weaknesses in drug management were often exposed, with additional complications if local manufacturing was required. Best practices for regimen change included early engagement of budgeting staff, procurement staff, regulators and manufacturers. Future decision makers will benefit from strengthened decision-making bodies, patient input, early and comprehensive planning, and regimens and evidence that address local, practical implementation issues.