This study was performed to determine the trends in seroprevalence of four major sexually transmitted infections (STIs) (HIV, hepatitis B virus (HBV), herpes simplex virus type 2 (HSV-2), and syphilis) over a 10-year period (2005-2014) in pregnant women in Ethiopia. Pregnant women (15-49 years old) who were enrolled in the antenatal care-based national HIV surveillance were included. Serological tests for HIV, HBV, HSV-2, and syphilis were done on serum/plasma samples. A total of 4887 pregnant women were included. Results showed a decline in prevalence of these STIs by 40-60% over the 10 years (2005-2014): HIV (10.5% to 5.5%), syphilis (2.5% to 1.1%), HBV (12.6% to 6.7%), and HSV-2 (47.5% to 28.5%). In 2014, 109/4887 (2.2%) women had triple infections. In 2005, 2007, and 2009, the prevalence of HSV-2 in the older age group (35-45 years) (47.1%, 47.4%, and 50.0%, respectively) was higher than that in the younger age group (15-24 years) (40.9%, 19.5%, and 20.2%, respectively). Age category (Chi-square=22.4, p40% was seen over the years in Ethiopia. However, an intermediate endemicity level of HBV and higher prevalence of HIV and HSV-2 by 2014, suggest the need to strengthen prevention strategy for STIs.