Oral lichen planus (OLP) is a cell-mediated inflammatory mucosal disorder and is classified as an oral potentially malignant disorder. Some research has shown that apoptosis in OLP cells is similar to a viral infection such as human papillomavirus (HPV). So, the aim of this case-control study was to investigate the association of high-risk HPV with OLP. DNA was extracted from 25 formalin-fixed, paraffin-embedded (FFPE) OLP tissues and 25 FFPE normal oral tissues as case and control groups, respectively. The presence of high-risk HPV16 and HPV18 DNA was investigated by polymerase chain reaction (PCR). p-value<.05 was considered significant. Twelve samples (48%) of OLPs were positive for HPV16, compared with six samples (24%) of controls; although the difference was not significant, it was borderline (p = .07). Three samples (12%) of OLPs were positive for HPV18 compared with one sample (4%) of controls; the difference was not significant (p = .3). The total frequency of both high-risk HPV were 14 samples (56%) of OLPs and 7 samples (28%) of controls; there was a significant association between the high-risk HPV and OLP (p = .04). High-risk HPVs was more prevalent in erosive-atrophic (EA) form of OLP as compared to non-EA form, although the difference was not significant (p = .13). The results suggest a significant association between high-risk HPVs and OLP.