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Previous studies suggested that helicase–primase inhibitor (HPI) resistance mutations can be selected at relatively high frequency from some isolates of herpes simplex virus type 1 (HSV-1). An intentional mismatch primer (IMP) PCR was developed to detect three known HPI resistance mutations well above the expected background frequency. The objective of this study was to provide proof that HPI resistance mutations pre-exist at relatively high frequency in some clinical isolates obtained from individuals naive to HPIs.Three different IMP PCRs were standardized to detect critical HPI resistance mutations (K356N or K356T in UL5, or A899T in UL52) at 10–100 times the expected background frequency (<10−6). Thirty HSV-1 clinical isolates were then screened for the resistance mutations in the absence of the inhibitor using IMP PCR.Among 30 clinical isolates that were all susceptible to the HPI, BAY 57–1293, 5 were shown to contain UL5 mutations at 10–100 times higher than the expected frequency. No UL52 resistance mutations were encountered in this study.The detection of HPI-resistant mutations in some clinical isolates by means of IMP PCR proved that the mutations pre-exist and showed that they are not induced during incubation with the inhibitor.