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Millions of cases of sexually transmitted infections (STIs) occur in the United States each year, resulting in substantial medical costs to the nation. Previous estimates of the total direct cost of STIs are quite dated. We present updated direct medical cost estimates of STIs in the United States.We assembled recent (i.e., 2002–2011) cost estimates to determine the lifetime cost per case of 8 major STIs (chlamydia, gonorrhea, hepatitis B virus, human immunodeficiency virus (HIV), human papillomavirus, genital herpes simplex virus type 2, trichomoniasis and syphilis). The total direct cost for each STI was computed as the product of the number of new or newly diagnosed cases in 2008 and the estimated discounted lifetime cost per case. All costs were adjusted to 2010 US dollars.Results indicated that the total lifetime direct medical cost of the 19.7 million cases of STIs that occurred among persons of all ages in 2008 in the United States was $15.6 (range, $11.0–$20.6) billion. Total costs were as follows: chlamydia ($516.7 [$258.3–$775.0] million), gonorrhea ($162.1 [$81.1–$243.2] million), hepatitis B virus ($50.7 [$41.3–$55.6] million), HIV ($12.6 [$9.5–$15.7] billion), human papillomavirus ($1.7 [$0.8–$2.9] billion), herpes simplex virus type 2 ($540.7 [$270.3–$811.0] million), syphilis ($39.3 [$19.6–$58.9] million), and trichomoniasis ($24.0 [$12.0–$36.0] million). Costs associated with HIV infection accounted for more than 81% of the total cost. Among the nonviral STIs, chlamydia was the most costly infection.Sexually transmitted infections continue to impose a substantial cost burden on the payers of medical care in the United States. The burden of STIs would be even greater in the absence of STI prevention and control efforts.