A significant association exists between the use of epidural morphine (EM), reactivation of herpes labialis (HL) commonly known as coldsores, and pruritus in the obstetric population. A randomized prospective study was designed to eliminate previously identified confounding variables. Immediately following delivery, parturients having undergone cesarean section with epidural anesthesia with carbonated lidocaine (Xylocaine® CO2, Astra, Mississauga, Ontario, Canada) with 1:200,000 epinephrine were sequentially randomized to receive either EM or im opioids for postoperative analgesia. One blood sample was collected for viral serology and two mouthwashes (day 0 and 2) were collected to determine oral viral shedding. The patients were observed daily for 5 days. Coldsores were cultured for herpes simplex virus (HSV). Of 187 patients, 96 received EM and 91 im opioids; herpes labialis occurred in 14 of 96 (14.6%) of the former but in 0 of 91 of the latter (P= 0.0004). All 14 experienced facial pruritus. The two groups were at equal risk for reactivation (seropositivity 64.6% and 62.6%, respectively). Analysis of data for those with positive HSV serology reveals 14 of 62 (22.5%) had EM and herpes labialis compared with 0 of 57 in the im group (P< 0.0001). The incidence of oral viral shedding was low. Surgical stress, the local anesthetic solution, and epinephrine addition to the local anesthetic were eliminated as confounders. Stepwise logistic regression analysis revealed that EM and a history of herpes labialis in these patients were predictive for reactivating oral HSV.