Background: Colon cancer incidence and mortality rates are increasing in low- and middle-income countries, such as South Africa (SA). Adjuvant chemotherapy after curative resection for stage III colon cancer prolongs overall survival, but it is unclear which regimen is most cost-effective in resource-constrained settings, such as the SA public healthcare system. Methods: A decision-analytic Markov model was developed to compare lifetime costs and health outcomes for 60-year-old stage III colon cancer patients treated with six adjuvant chemotherapy regimens in a public hospital in SA: fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for 3 and 6 months, capecitabine and oxaliplatin (CAPOX) for 3 and 6 months, capecitabine for 6 months, and fluorouracil/leucovorin (5-FU/LV; Mayo regimen) for 6 months. Transition probabilities were derived from clinical trials to estimate risks of toxicity, disease recurrence, and survival. Costs from a SA societal perspective and utility estimates were obtained from literature and local expert opinion. The primary outcome was the incremental cost-effectiveness ratio (ICER) in international dollars (I$) per disability-adjusted life year (DALY) averted, with a willingness-to-pay (WTP) threshold of one times the 2020 GDP per capita of SA (I$13,006.57; ZAR89,225). Results: Our model found CAPOX for 3 months to be the most cost-effective strategy, at a lifetime cost below the local WTP threshold (I$5,380.82; ZAR36,912.44) and 5.74 DALYs averted, compared to no chemotherapy. FOLFOX for 6 months was also on the efficiency frontier, with a higher total cost (I$22,747.47; ZAR156,047.64) and 0.18 additional DALYs averted (ICER = I$99,021.35/DALY averted). All other strategies were absolutely dominated. One-way sensitivity analyses found that FOLFOX for 6 months is optimal when the administration cost (i.e.: port and pump) falls to 20% of the base case price. Conclusions: In the SA public healthcare system, CAPOX for 3 months is the most cost-effective adjuvant treatment for stage III colon cancer. FOLFOX for 6 months, with a greater effectiveness, may be cost-effective if the administration cost decreases significantly. The optimal strategy in other settings may vary according to the local WTP threshold.

^aI$1.00 = ZAR6.86 (estimated 2020 Purchasing Power Parity for SA). ^bIn I$ per DALY averted relative to the optimal strategy.