Despite a strong association of detection of human papillomavirus (HPV) by polymerase chain reaction with prognosis in invasive cervical cancer, no previous studies have considered sequencing efforts. In this study, the association was assessed when also including comprehensive analysis of HPV infection by deep sequencing and a longer follow-up period.

• RNA sequencing on the NovaSeq 6000 platform (Illumina) was conducted in all 392 of 2,845 invasive cervical cancer cases that were polymerase chain reaction–negative for HPV, which led to identification of an additional 169 cases as HPV-positive.

• A 43% reduction in excess mortality was observed in correlation with high-risk [hr] HPV-positive ICC when compared with HPV-sequence–negative or polymerase chain reaction-hrHPV–negative ICC.

• Across cancer stages, histologic types, and other clinical characteristics, the mortality reduction consistently remained evident.

• For patients with cervical cancer, researchers suggest the value of tumor hrHPV status as a novel biomarker with strong prognostic value.

• Consideration should be given to introducing HPV testing of cervical tumors in routine clinical workup of cervical cancer, to improve prognostic information for clinicians and women.