Background: The significant number of qualitative and quantitative ultrasound markers described for first-trimester screening of open spina bifida (OSB) and other posterior brain defects (oPBD) has resulted in their complex implementation and interpretation for a widespread screening and in a lack of consensus regarding diagnostic accuracy. Objectives: To assess and compare the accuracy of qualitative and quantitative cranial sonographic markers at 11-14 weeks of gestation for the detection of OSB and oPBD. Search strategy: A systematic literature search was performed in MEDLINE and COCHRANE from 2009 to April 2020. Selection criteria: Studies assessing the diagnostic accuracy of quantitative and/or qualitative ultrasound signs to predict OSB and oPBD were included. Cohort studies and case-control studies were also considered. Data collection and analysis: Two reviewers independently extracted data and assessed the risk of bias. The overall pooled estimate and a summary receiver operating characteristic curve was estimated for each subgroup (qualitative and quantitative assessment). Main results: Twenty-three studies were included in our meta-analysis. The pooled sensitivity and specificity for qualitative assessment were 76.5% and 99.6%, and for quantitative assessment were 84.5% and 96.3%, respectively; specificity for the qualitative ultrasound signs was significantly higher (P = 0.001). The overall sensitivity of cranial sonographic markers for the screening of oPBD was 76.7% and specificity was 97.5%. Conclusions: The qualitative approach demonstrated greater specificity, so this would appear to be more appropriate for daily screening, as a first-line tool, whereas the quantitative approach should be reserved for expert ultrasound. Tweetable abstract: This study highlights the relevance of first-trimester qualitative ultrasound signs in the screening of open spina bifida.