Objective The aim of this paper is to assess to what extent a Skilled Care Initiative (SCI) was associated with pregnancy-related mortality in Ouargaye district, Burkina Faso. Methods We used a quasi-experimental design to compare pregnancy-related mortality within the intervention district (health facility areas covered by the SCI vs. areas not covered) and between the intervention district (Ouargaye) and a comparison district (Diapaga). Population-based data were used to examine differences in pregnancy-related mortality levels, their determinants and how they related to uptake of care, as well as examining contexts and mechanisms of pregnancy-related deaths that occurred. Data analyses included descriptive statistics, univariate and multivariate regression analyses. Results The main risk factors for pregnancy-related mortality in rural Burkina Faso were age (extreme ages of reproductive period), low coverage of antenatal care and low institutional delivery. The introduction of the SCI, as implemented within the study reference period, had no appreciable effect on pregnancy-related mortality. Conclusion Although the SCI was conceptually well designed and implemented, structural constraints may have limited its effectiveness for reducing pregnancy-related mortality within its period of implementation. Lessons have been identified which might enable similar skilled attendance strategies to make their full potential impact on pregnancy-related mortality in remote and rural settings.