Human papillomavirus (HPV) is a major cause of cervical neoplasia development. HPV screening is very important because early treatment can prevent cervical cancer. Omniplex-HPV is a polymerase chain reaction followed by Luminex xMAP bead microarray technology that is designed for detecting 40 HPV genotypes. The aim of this study is to evaluate the analytical and clinical performance of the Omniplex-HPV in comparison with that of the commercially available RFMP (restriction fragment mass polymorphism) HPV PapilloTyper. A total of 2,808 cervical swab specimens were obtained. Of these, only 1799 specimens had a cytology result. A type-specific direct sequencing test was performed using the reference method in case of discrepancies between the two test results. The overall percent agreement (OPA) between Omniplex-HPV and RFMP HPV PapilloTyper was 97.9% (κ=0.84; 95% CI: 0.81-0.88). The positive percent agreement (PPA) and the negative percent agreement (NPA) were 98.0% and 96.2%, respectively. The Omniplex-HPV and RFMP HPV PapilloTyper showed comparable sensitivities (90.2% and 91.9%, respectively) and specificities (91.3% each), while the Omniplex-HPV produced more accurate results and required less turnaround time and labor. The agreement between these two methods was excellent for HPV genotyping (P>0.05; McNemar's test), and clinical sensitivity, specificity, and odds ratio of the two assays were comparable to the result of cytology tests in identifying high risk HPV. In conclusion, Omniplex-HPV and RFMP HPV PapilloTyper were highly comparable with regard to detection and genotyping analysis of HPV.