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Background A decade after South Africa adopted tuberculosis preventive therapy (TPT), uptake remains sub-optimal.Methods Senior nurses at primary care clinics participated in semistructured individual interviews. Transcripts were thematically analysed to assess knowledge and attitudes towards TPT in rural South Africa.Results Among 22 senior nurses, 86% were female, with the median age of 39 years, and mean of 13.3 years’ experience. Participants identified key individual-level barriers among nurses, interpersonal barriers that nurses observed among their patients and organisational barriers. While the nurses’ belief in TPT efficacy was strong, their perceived barriers to TPT implementation included inflexible clinical guidelines, insufficient training and time to counsel patients, pill burden, patients’ perceived HIV stigma and patients’ alcohol use. Nurses believed implementation could be facilitated with task-shifting and integrating TPT into the antiretroviral (ART) infrastructure in primary care clinics and into chronic medication dispensing programmes. Shorter TPT regimens (eg, 12 weeks weekly INH/rifapentine: 3HP) were considered advantageous.Conclusions Nurses identified multiple barriers to TPT implementation, including insufficient training and time to counsel patients, pill burden, HIV stigma and alcohol use. Nurses suggested task-shifting, TPT/ART integration and rollout of 3HP as potential facilitators of TPT implementation in rural South Africa. Nurses’ perspectives are essential to informing TPT implementation efforts in resource-limited settings.