This study was designed to evaluate a possible association between reactivated herpes simplex virus type 1 (HSV-1) infection after lower third molar extraction and development of dry socket (DS). The HSV-1 antibody response was analyzed before and after tooth removal by enzyme-linked immunosorbent assay and immunoblotting in 208 patients. History of previous possible oral herpes reactivation was evaluated by a questionnaire that was based on self-rated frequency of oral cold sores. Tobacco users were identified. The anatomic proximity of the root apex to the mandibular nerve canal was classified radiographically before extraction. Fifteen patients (7%) developed DS after tooth extraction. Eleven of the 15 DS patients (73%) were HSV seropositive as compared with 7 of 15 (47%) in the matched control group. Seven of the 11 seropositive DS patients have shown HSV-1 reactivation by an increase of specific polypeptides, predominantly gB, gC, gD and ICP 4 and 6, in the immunoblot test. No change in HSV-1 reactivity was observed in control sera. DS patients reported a high frequency of oral cold sores (64%) compared with the controls (33%). Tobacco use was not found to influence the frequency of cold sores or the development of DS. A close radiographic proximity between the mandibular canal and root apex was more common (P < .05) in DS patients. The results indicate that extraction of a mandibular third molar could be a possible cause of reactivation and recurrence of an HSV-1 infection.(ABSTRACT TRUNCATED AT 250 WORDS)