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Zika virus (ZIKV) emerged in Brazil during 2013–2014 causing an epidemic of previously unknown congenital abnormalities. The frequency of severe congenital abnormalities after maternal ZIKV infection revealed an unexplained geographic variability, especially between the Northeast and the rest of Brazil. Several reasons for this variability have been discussed. Prior immunity against DENV, that affects ZIKV seems to be the most likely explanation. Here we summarise the current evidence regarding the prominent co-factor to potentially explain the geographic variability. This systematic review followed the PRISMA guidelines. The search was conducted up to May 15th, 2020, focussing on immunological interactions from Zika virus with previous Dengue virus infections as potential teratogenic effect for the foetus. Eight out of 339 screened studies reported on the association between ZIKV, prior Dengue virus infection and microcephaly, mostly focusing on antibody-dependent enhancement (ADE) as potential pathomechanism. Prior DENV infection was associated with enhancement for ZIKV infection and increased neurovirulence in one included in vitro study only. Interestingly, the seven in vivo studies exhibited a heterogeneous picture with three studies showing a protective effect of prior DENV infections and others no effect at all. According to several studies, socio-economic factors are associated with increased risk for microcephaly. Very few studies addressed the question of unexplained variability of infection-related microcephaly. Many studies focussed on ADE as mechanism without measuring microcephaly as endpoint. Interestingly, three of the included studies reported a protective effect of prior DENV infection against microcephaly. This systematic review strengthens the hypothesis that immune priming after recent DENV infection is the crucial factor for determining protection or enhancement activity. It is of high importance that the currently ongoing prospective studies include a harmonized assessment of the potential candidate co-factors. Author summary: Despite the large volume of Zika virus (ZIKV)-related research, the difference in the distribution of the frequency of ZIKV-related severe congenital abnormalities between Northeastern Brazil in the rest of Brazil and other locations has not been adequately explained. This systematic review summarizes the existing evidence for the role of prior Dengue virus (DENV) infections as co-factor to explain the variability in the frequency of ZIKV-related severe congenital abnormalities. Results differed significantly according to study type (e.g. in vitro versus in vivo studies), and no clear picture emerged with regard to prior DENV infections causing ZIKV-related severe congenital abnormalities. Studies that did not include these abnormalities as outcomes were not included. However, evidence from some of these additional studies that focus on immunological interactions between DENV and ZIKV infections imply the potential that severe ZIKV disease is more frequent in those with prior DENV infections. Therefore, an assessment of background immunity against closely related viruses (e.g. the flavivirus family) needs to be included in future and ongoing longitudinal studies on ZIKV-related congenital abnormalities. [ABSTRACT FROM AUTHOR]