Objectives This study examined significant caries (SiC) and the interactive effects of maternal-related oral hygiene factors in urban preschool children. Methods A cross-sectional study was designed to collect data from a cluster of randomly selected samples in 2011. A total of 495 child-mother pairs from the San-Ming District of Kaohsiung City, Taiwan, participated in the study. Children aged 4-6 years received dental examinations, and their mothers completed a self-administered questionnaire. The SiC Index indicated the highest caries values in participants. The association between 3 groups – dmft (decayed, missing, and filled teeth)-free, non-SiC, and SiC – and the mothers’ and their children’s factors were examined using polytomous logistic regression analysis. Results Among the SiC children, caries experience was most frequent in the mandibular molars (64.5-84.9 percent), and almost 50 percent of these children had central incisor caries. The significant factors associated with the SiC children were lower maternal self-efficacy in oral hygiene [adjusted odds ratio (aOR) = 2.04], child’s intake of sugar-sweetened beverages (SSBs) more than once per day (aOR = 2.27), and irregular child dental checkups (aOR = 2.32). Significant interaction effects were detected among children who received irregular dental checkups and whose SSBs intake was more than once per day and whose mothers had lower self-efficacy in oral hygiene (P for interaction term = 0.034 and 0.004, respectively). Conclusions Caries prevention programs should prioritize enhancing maternal self-efficacy in oral hygiene and emphasize childhood SSBs intake management and regular dental checkups to mothers to prevent severe caries in preschool-aged children.