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Background: Malaria is a major cause of morbidity and mortality globally, especially in sub-Saharan Africa. Widespread resistance to pyrethroids threatens the gains achieved by vector control. To counter resistance to pyrethroids, third-generation indoor residual spraying (3GIRS) products have been developed. This study details the results of a multi-country cost and cost-effectiveness analysis of indoor residual spraying (IRS) programmes using Actellic ® 300CS, a 3GIRS product with pirimiphos-methyl, in sub-Saharan Africa in 2017 added to standard malaria control interventions including insecticide-treated bed nets versus standard malaria control interventions alone., Methods: An economic evaluation of 3GIRS using Actellic ® 300CS in a broad range of sub-Saharan African settings was conducted using a variety of primary data collection and evidence synthesis methods. Four IRS programmes in Ghana, Mali, Uganda, and Zambia were included in the effectiveness analysis. Cost data come from six IRS programmes: one in each of the four countries where effect was measured plus Mozambique and a separate programme conducted by AngloGold Ashanti Malaria Control in Ghana. Financial and economic costs were quantified and valued. The main indicator for the cost was cost per person targeted. Country-specific case incidence rate ratios (IRRs), estimated by comparing IRS study districts to adjacent non-IRS study districts or facilities, were used to calculate cases averted in each study area. A deterministic analysis and sensitivity analysis were conducted in each of the four countries for which effectiveness evaluations were available. Probabilistic sensitivity analysis was used to generate plausibility bounds around the incremental cost-effectiveness ratio estimates for adding IRS to other standard interventions in each study setting as well as jointly utilizing data on effect and cost across all settings., Results: Overall, IRRs from each country indicated that adding IRS with Actellic ® 300CS to the local standard intervention package was protective compared to the standard intervention package alone (IRR 0.67, [95% CI 0.50-0.91]). Results indicate that Actellic ® 300CS is expected to be a cost-effective (> 60% probability of being cost-effective in all settings) or highly cost-effective intervention across a range of transmission settings in sub-Saharan Africa., Discussion: Variations in the incremental costs and cost-effectiveness likely result from several sources including: variation in the sprayed wall surfaces and house size relative to household population, the underlying malaria burden in the communities sprayed, the effectiveness of 3GIRS in different settings, and insecticide price. Programmes should be aware that current recommendations to rotate can mean variation and uncertainty in budgets; programmes should consider this in their insecticide-resistance management strategies., Conclusions: The optimal combination of 3GIRS delivery with other malaria control interventions will be highly context specific. 3GIRS using Actellic ® 300CS is expected to deliver acceptable value for money in a broad range of sub-Saharan African malaria transmission settings., (© 2022. The Author(s).)