Background: Cervical cancer screening programs are facing a programmatic shift where screening protocol based on human papillomavirus testing (HPV-Screening protocol) is replacing the liquid-based cytology (LBC-Screening protocol). For safe technology transfer within the nationwide screening programme in Norway, HPV-Screening protocol was implemented randomized to compare the real-world effectiveness of HPV-Screening protocol and LBC-Screening protocol at the first screening round. Methods: Among 302 295 women aged 34-69 years scheduled to attend screening from February 2015 to June 2017, 157 447 attended. 77 207 were randomly allocated to the HPV-Screening protocol and 80 240 were allocated to the LBC-Screening protocol. All women were followed up for 18 months. Results: The HPV-Screening protocol resulted in a relative increase of 60% in the detection of cervical intraepithelial neoplasia grade 2 or worse (risk ratio [RR] = 1.6, 95% confidence interval [CI] = 1.5-1.7), 40% in CIN grade 3 or worse (RR = 1.4, 95%CI = 1.3-1.6), 40% in cancer (RR = 1.4, 95%CI = 1.0-2.1) and 60% in colposcopy referrals (RR = 1.6, 95%CI = 1.5-1.6) compared to LBC-Screening. The performance of both protocols was age-dependent, being more effective in women aged under 50 years. Conclusions: The HPV-Screening protocol was well accepted by women in Norway and detected more CIN2, CIN3 and cancers compared to the LBC-Screening protocol. Impact: A randomized implementation of the HPV-Screening protocol with real-world assessment enabled a gradual, quality assured and safe technology transition. HPV-based screening protocol may further be improved by using HPV genotyping and age-specific referral algorithms.