The clinical performance evaluation of the novel MassARRAY human papillomavirus (MA-HPV) assay was performed using Danish SurePath cervical cancer screening samples under the fourth Validation of HPV Genotyping Tests (VALGENT) framework. The MA-HPV assay is a mass array-based assay that individually detects 14 oncogenic HPV genotypes and five nononcogenic types. The MA-HPV assay was validated using the VALGENT4 panel, which constitutes 997 consecutive samples from a screening population in addition to 297 disease-enriched samples with abnormal cytology findings. The clinical accuracy of the MA-HPV assay for sensitivity and specificity was assessed relative to that of the general primer 5+/6+ PCR enzyme immunoassay (GP-EIA), by a noninferiority test. The type-specific concordance of the MA-HPV assay was assessed as well. The relative sensitivity of the MA-HPV assay for cervical intraepithelial neoplasia ≥2 or ≥3 was 1.02 (95% CI, 0.98-1.05) and 1.01 (95% CI, 0.99-1.04), respectively. The sensitivity of the MA-HPV was noninferior to that of the GP-EIA (P = 0.0001), whereas the specificity of the MA-HPV was inferior (0.89; 95% CI, 0.85-0.91; P > 0.99). The MA-HPV assay is a clinical sensitive assay with a lower clinical specificity compared with the GP-EIA. The assay in its current form seems more suited to play a role where specificity is of lesser importance but where high sensitivity is paramount.