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<p><b>BACKGROUND: </b>To evaluate the performance and to identify predictive factors of performance in prevention of mother-to-child HIV transmission programs (PMTCT) in sub-Saharan African countries.</p><p><b>METHODS: </b>From 2000 to 2011, PMTCT programs included in the Viramune Donation Programme (VDP) were prospectively followed. Each institution included in the VDP provided data on program implementation, type of management institution, number of PMTCT sites, key programs outputs (HIV counseling and testing, NVP regimens received by mothers and newborns). Nevirapine Coverage Ratio (NCR), defined as the number of women who should have received nevirapine (observed HIV prevalence x number of women in antenatal care), was used to measure performance. Included programs were followed every six months through progress reports.</p><p><b>RESULTS: </b>A total of 64 programs in 25 sub-Saharan African countries were included. The mean program follow-up was 48.0 months (SD = 24.5); 20,084,490 women attended in antenatal clinics were included. The overall mean NCR was 0.52 (SD = 0.25), with an increase from 0.37 to 0.57 between the first and last progress reports (p<.0001); NCR increased by 3.26% per year-program. Between the first and the last report, the number of women counseled and tested increased from 64.3% to 86.0% (p<.0001), the number of women post-counseled from 87.5% to 91.3% (p = 0.08). After mixed linear regression analysis, type of responsible institution, number of women attended in ANC, and program initiation in 2005-2006 were significant predictive factors associated with the NCR. The effect of the time period increased from earlier to later periods.</p><p><b>CONCLUSION: </b>A longitudinal assessment of large PMTCT programs shows that scaling-up of programs was increased in sub-Saharan African countries. The PMTCT coverage increased throughout the study period, especially after 2006. Performance may be better for programs with a small or medium number of women attended in ANC. Identification of factors that predict PMTCT program performance may help in the development and expansion of additional large PMTCT services in sub-Saharan Africa.</p>