Cervical screening with human papillomavirus (HPV) testing is less specific for high-grade cervical intraepithelial neoplasia (≥CIN3) than cytology. The aim of this systematic review was to determine whether a restriction of HPV testing to women aged at least 30 years would eliminate the problem. On the basis of the data from randomized controlled trials, we calculated the relative detection of CIN1 and CIN2, and the relative risks of false-positive tests (positive tests without subsequent ≥CIN3) per age group and trial for HPV testing versus cytology. For women aged at least 30 years in trials with a low cytology abnormality rate, detection of CIN1 increased significantly by 50–90% in the two trials with reported data; detection of CIN2 was doubled in three trials; the risks of false-positive HPV tests were also doubled. In trials with a high cytology abnormality rate, these risks were similar for HPV testing and cytology. Adverse effects of HPV testing were for both types of cytology settings, generally higher for women below than above the age of 30. Adverse effects were less common among women aged at least 30 years than among younger women. However, in older women HPV testing still led to more CIN1/CIN2 diagnoses and false-positive tests than cytology.