BACKGROUND: Afghanistan has one of the highest rates of maternal mortality in the world. We assess the health outcomes and cost-effectiveness of strategies to improve the safety of pregnancy and childbirth in Afghanistan. METHODS: Using national and sub-national data, we adapted a previously validated model that simulates the natural history of pregnancy and pregnancy-related complications. We incorporated data on antenatal care, family planning, skilled birth attendance and information about access to transport, referral facilities and quality of care. We evaluated single interventions (e.g. family planning) and strategies that combined several interventions packaged as integrated services (transport, intrapartum care). Outcomes included pregnancy-related complications, maternal deaths, maternal mortality ratios, costs and cost-effectiveness ratios. FINDINGS: Model-projected reduction in maternal deaths between 1999-2002 and 2007-08 approximated 20%. Increasing family planning was the most effective individual intervention to further reduce maternal mortality; up to 1 in 3 pregnancy-related deaths could be prevented if contraception use approached 60%. Nevertheless, reductions in maternal mortality reached a threshold (∼30% to 40%) without strategies that assured women access to emergency obstetrical care. A stepwise approach that coupled improved family planning with incremental improvements in skilled attendance, transport, referral and appropriate intrapartum care and high-quality facilities prevented 3 of 4 maternal deaths. Such an approach would cost less than US$200 per year of life saved at the national level, well below Afghanistan's per capita gross domestic product (GDP), a common benchmark for cost-effectiveness. Similar results were noted sub-nationally. INTERPRETATION: Our findings reinforce the importance of early intensive efforts to increase family planning for spacing and limiting births and to provide control of fertility choices. While significant improvements in health delivery infrastructure will be required to meet Millennium Development Goal 5, a paced systematic effort that invests in scaling up capacity for integrated maternal health services as the total fertility rate declines appears feasible and cost-effective.