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Nigeria has high rates of mother-to-child HIV transmission. We sought to determine whether new WHO recommendations for long-course antiretroviral therapy (ART) prophylaxis are cost-effective for prevention of mother-to-child transmission (PMTCT) of HIV compared to short-course strategies in Nigeria.We conducted a cost-effectiveness analysis from a health-system perspective, with a target population consisting of HIV-infected pregnant women in Nigeria.A decision-analysis model compared two strategies for PMTCT: intervention – long-course maternal triple ART [zidovudine/lamivudine/efavirenz (ZDV/3TC/EFV)] beginning at 14 weeks gestation through the end of breastfeeding, with infant ART, per new WHO guidelines (option B); and minimal standard of care (MSOC) in Nigeria – short-course dual ART (ZDV/3TC) from 34 weeks gestation to 1 week postpartum, with single-dose nevirapine for infant and mother at labor/delivery. The primary outcomes were expected costs, pediatric HIV cases, and disability-adjusted life years (DALYs) accrued with each strategy; cost-effectiveness was represented using incremental cost-effectiveness ratios (ICERs).If implemented at the level of antenatal coverage in Nigeria (58%), mother-to-child HIV transmission could be reduced to 16.1% with MSOC and 12.8% with the intervention. At current pregnancy rates, the intervention would prevent 7680 infant HIV cases and avert 230 400 DALYs annually, compared to MSOC. The average health-system cost of the intervention was US$ 401 per pregnancy compared to $293 per pregnancy with MSOC. The intervention was associated with an ICER of $113 per-DALY-averted compared to MSOC, and was highly cost-effective using a willingness-to-pay threshold of per-capita Nigerian GDP.Implementation of new WHO recommendations for extended maternal and infant prophylaxis is highly cost-effective compared to short-course regimens for PMTCT of HIV in Nigeria.