INTRODUCTIONEnvironmental tobacco smoke (ETS) is associated with several congenital anomalies, including non-syndromic orofacial clefts (NSOFCs). This systematic review aimed to update the literature on the association between ETS and NSOFCs.METHODSFour databases were searched up to March 2022, and studies that evaluated the association between ETS and NSOFCs were selected. Two authors selected the studies, extracted the data, and evaluated the risk of bias. Comparing the association of maternal exposure to ETS and active parental smoking with NSOFCs allowed for the creation of pooled effect estimates for the included studies.RESULTSTwenty-six studies were deemed eligible for this review, of which 14 were reported in a previous systematic review. Twenty five were case-control studies, and one was a cohort study. In total, these studies included 2142 NSOFC cases compared to 118129 controls. All meta-analyses showed an association between ETS and the risk of having a child with NSOFC, based on the cleft phenotype, risk of bias, and year of publication, with a pooled increased odds ratio of 1.80 (95% CI: 1.51–2.15). These studies had a marked heterogeneity, which decreased upon subgrouping based on the recent year of publication and the risk of bias.CONCLUSIONSETS exposure was associated with more than a 1.5-fold increase in the risk of having a child with NSOFC, showing a higher odds ratio than paternal and maternal active smoking.TRIAL REGISTRATIONThe study is registered on the International Prospective Register of Systematic Reviews database # CRD42021272909.