More HIV-infected women in need of services for the prevention of mother-to-child transmission of HIV (PMTCT) give birth in Nigeria than in any other nation in the world. To meet the UNAIDS/WHO goal of eliminating mother-to-child HIV transmission by 2015, multiple interventions will be required to scale up PMTCT services, especially to lower-level, rural health facilities. To address this, we are conducting a cluster-randomized controlled study to evaluate the impact and cost-effectiveness of a novel, family-focused integrated package of services for PMTCT. A systematic reassignment of patient care responsibilities coupled with the adoption of point-of-care CD4+ cell count testing could facilitate the ability of lower-cadre health providers to manage PMTCT care, including the provision and scale-up of antiretroviral therapy to pregnant women in rural settings. Additionally, as influential community members, male partners could support their partners’ uptake of and adherence to PMTCT care. We describe an innovative approach to scaling up PMTCT service provision that incorporates considerations of where and from whom women can access services (task-shifting), ease of obtaining a CD4 result (point-of-care testing), the degree of HIV service integration for HIV-infected women and their infants, and the level of family and community involvement (specifically male partner involvement). This systematic approach, if proven feasible and effective, could be scaled up in Nigeria and similar resource-limited settings as a means to accelerate progress toward eliminating mother-to-child transmission of HIV and help women with HIV infection live long, healthy lives (Trial registration: NCT01805752).