Objective To apply rapid prototyping (RP) technology on pre-fabricating nasoalveolar molding (NAM) appliances, and compare clinical outcomes and complications with traditional NAM appliances. Methods Between June 2014 and September 2016, 39 children with unilateral cleft lip and palate were included in study. Seventeen children (test group) had received novel NAM protocol by pre-fabricating NAM appliances using RP technology, and the other 22 children (control group) had received traditional NAM protocol. There was no significant difference in gender, age, the side of cleft lip and palate, and the width of the alveolar cleft gap before treatment between 2 groups (P>0.05). The change of width of the alveolar cleft gap, number of clinic visit, treatment time, and complications were compared between 2 groups. Results The number of clinic visit was less in test group than in control group (P<0.05). There was no significant difference in treatment time between 2 groups (P>0.05). During treatment, there was 16 children (72.2%) of skin irritation, 3 (13.6%) of mucosal ulceration, 1 (4.5%) of intraoral bleeding, 1 (4.5%) of alveolar arch T-shap asymmetry in control group. And there were 11 children (64.7%) of skin irritation, 3 (17.6%) of mucosal ulceration in test group. There was no significant difference in the incidence of complications between 2 groups (P>0.05). After treatment, the anterior alveolar cleft width, horizontal cleft width, sagittal cleft width, antero-medial alveolar ridges angle of the healthy side, angle between anterior alveolar and posterior alveolar baseline of the healthy side, perpendicular distance from buccal frenum point to sagittal line were significantly reduced when compared with the values before treatment (P<0.05). The angle between the anterior segments of two sides, angle between buccal frenum point and posterior baseline were significant increased when compared with the values before treatment (P<0.05). There was no significant difference in the differences between pre- and post-treatment of above indexes between 2 groups (P>0.05). There also was no significant difference in posterior alveolar width, the width between the middle parts of alveolar, vertical cleft width, antero-medial alveolar ridges angle of the affected side, and angle between anterior alveolar and posterior alveolar baseline of the affected side between pre- and post-treatment in each group (P>0.05). Conclusion Clinical outcome of novel approach was equivalent to traditional protocol; however, the number of clinic visit decreased. With improving of RP technology, it would provide a more consistency and convenient way for sequential treatment with cleft lip and palate.