Objective. This systematic review evaluates the accuracy of the mRNA HPV biomarker in cervical smears to identify cervical intraepithelial neoplasia (CIN) 2 or 3 and cervical cancer. Data Source. Eligible studies were identified by performing a search of electronic databases on Medline via Pubmed, Lilacs, Cochrane Library, Embase, and Grey literature for papers published between January 1990 and June 2018. Study Eligibility Criteria. As no randomized studies were identified, this review focuses on observational studies in which the mRNA HPV diagnostic test was compared to a histopathology reference standard. We analyzed studies that included women screened for cervical cancer using mRNA HPV. Study Appraisal and Synthesis Methods. After screening, 61 studies including 29,674 patients met the inclusion criteria and were analyzed. Dichotomization was performed by defining CIN2 or worse (CIN2+) versus CIN1, HPV infection, and normal (CIN 1-). The analysis was discriminated by the following tests: Aptima, PreTect HPV Profeer, NucliSens EasyQ HPV, OncoTect, and Quantivirus. Results. Analyzing by technique, Aptima, with 28 studies, exhibited superior performance, showing for the outcomes CIN2+ and CIN3+ an AUC of 0.88 (0.82-0.95) and 0.91 (0.84-0.99), a pooled sensitivity of 92.8% (95%CI 91.9-93.7) and 95.6% (95%CI 94.5-96.5), and a pooled specificity of 60.5% (95%CI 59.8-61.3) and 61.9% (95%CI 61.1-62.7), respectively. Conclusion. This study supports the current hypothesis that the mRNA HPV assay is an adequate tool for secondary cervical cancer screening.