Background: There is growing evidence regarding the potential of closed incision negative pressure wound therapy (ci-NPWT) to prevent surgical site infections (SSIs) in healing wounds by primary closure following a caesarean section (CS). Aim: To assess the cost-effectiveness of ci-NPWT compared to standard dressings for prevention of SSI in obese women giving birth by CS. Materials and Methods: Cost-effectiveness and cost-utility analyses from a health service perspective were undertaken alongside a multicentre pragmatic randomised controlled trial, which recruited women with a pre-pregnancy body mass index ≥30 kg/m2 giving birth by elective/semi-urgent CS who received ci-NPWT (n = 1017) or standard dressings (n = 1018). Resource use and health-related quality of life (SF-12v2) collected during admission and for four weeks post-discharge were used to derive costs and quality-adjusted life years (QALYs). Results: ci-NPWT was associated with AUD$162 (95%CI −$170 to $494) higher cost per person and an additional $12 849 (95%CI −$62 138 to $133 378) per SSI avoided. There was no detectable difference in QALYs between groups; however, there are high levels of uncertainty around both cost and QALY estimates. There is a 20% likelihood that ci-NPWT would be considered cost-effective at a willingness-to-pay threshold of $50 000 per QALY. Per protocol and complete case analyses gave similar results, suggesting that findings are robust to protocol deviators and adjustments for missing data. Conclusions: ci-NPWT for the prevention of SSI in obese women undergoing CS is unlikely to be cost-effective in terms of health service resources and is currently unjustified for routine use for this purpose.