BACKGROUND: Infections are a common complication of abdominal surgery in low- and middle-income countries (LMICs). The role of a high fraction of inspired oxygen (FiO2) and chlorhexidine mouthwash in preventing post-operative infections is unconfirmed. METHODS: Internal pilot phase of an international outcome assessor-blinded, 2x2 factorial randomised trial of patients aged ≥10-years undergoing midline laparotomy in LMIC hospitals. The main trial objectives are to compare the clinical effectiveness of preoperative 0.2% chlorhexidine mouthwash in preventing pneumonia versus no mouthwash, and 80-100% perioperative FiO2 to prevent surgical site infection (SSI) versus 21-35% FiO2. This 12-month internal pilot assessed feasibility of hospital site opening, patient recruitment, intervention adherence, patient follow-up and safety. Patients were randomised in a 1:1:1:1 ratio to the four intervention group combinations and followed up for 30 days. RESULTS: We recruited 927 patients from seven hospitals in India and South Africa over 12 months from November 2020. There were 907 adults (97.8%) and 20 children aged ten or over (2.2%): 89/927 (9.6%) patients died. Site opening reached 70% of our target (7/10) hospitals, and patient recruitment 107% (927/870). 917/927 (99%) patients in the mouthwash arm, and 840/927 (91%) patients in the oxygen arm received the allocated intervention. Lower adherence to the oxygen intervention related mainly to clinically necessary FiO2 increases in the 21-35% FiO2 arm. 30-day follow-up was completed appropriately for 924/927 (99%) patients. and was performed by a masked assessor for all patients. There were no reported safety events. CONCLUSION: This pilot showed the feasibility and safety of a major phase III trial in post-operative infection prevention in LMICs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04256798.