Abstract Background The HIV epidemic in Russia has increasingly involved reproductive-aged women, which may increase perinatal HIV transmission. Methods Standard HIV case-reporting and enhanced perinatal HIV surveillance systems were used for prospective assessment of HIV-infected women giving birth in St. Petersburg, Russia, during 2004-2008. Trends in social, perinatal, and clinical factors influencing mother-to-child HIV transmission stratified by history of injection drug use, and rates of perinatal HIV transmission were assessed using two-sided χ2 or Cochran-Armitage tests. Results Among HIV-infected women who gave birth, the proportion of women who self-reported ever using injection drugs (IDUs) decreased from 62% in 2004 to 41% in 2008 (P < 0.0001). Programmatic improvements led to increased uptake of the following clinical services from 2004 to 2008 (all P < 0.01): initiation of antiretroviral prophylaxis at ≤28 weeks gestation (IDUs 44%-54%, non-IDUs 45%-72%), monitoring of immunologic (IDUs 48%-64%, non-IDUs 58%-80%) and virologic status (IDUs 8%-58%, non-IDUs 10%-75%), dual/triple antiretroviral prophylaxis (IDUs 9%-44%, non-IDUs 14%-59%). After initial increase from 5.3% (95% confidence interval [CI] 3.5%-7.8%) in 2004 to 8.5% (CI 6.1%-11.7%) in 2005 (P < 0.05), perinatal HIV transmission decreased to 5.3% (CI 3.4%-8.3%) in 2006, and 3.2% (CI 1.7%-5.8%) in 2007 (P for trend <0.05). However, the proportion of women without prenatal care and without HIV testing before labor and delivery remained unchanged. Conclusions Reduced proportion of IDUs and improved clinical services among HIV-infected women giving birth were accompanied by decreased perinatal HIV transmission, which can be further reduced by increasing outreach and HIV testing of women before and during pregnancy.