Primary genital herpes simplex virus (HSV) infection is commonly associated with systemic symptoms. A systematic evaluation of HSV viremia during primary genital infection has not been performed previously. Plasma samples from adults with a first clinical episode of genital HSV infection were assayed for HSV DNA by polymerase chain reaction. One hundred sixty-four adults had confirmed primary genital HSV infection. Of these, 40 (24%) had HSV DNA detected in plasma. Thirty-seven (93%) of 40 were infected with HSV-2. Viremic participants were more likely to be women, compared with aviremic participants (83% vs. 61%; P=.01). Viremia was detected more frequently and at a higher number of copies per milliliter early in infection. We conclude that HSV viremia during primary genital HSV infection is common, especially among women.