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Objective This study investigates whether the use of acellular dermal matrix (ADM) affects the long-term speech outcomes in patients undergoing primary palatoplasty with radical intravelar veloplasty. Design Retrospective cohort study. Setting Tertiary university-affiliated hospital. Participants A consecutive cohort of 112 patients who underwent primary palatoplasty with radical intravelar veloplasty from August 2014 to March 2018 were included. Main outcome measures A 2 × 2 cm-sized ADM was incorporated as an interpositional graft between the oral and nasal lining at the soft-hard palate junction. The perceptual analysis of hypernasality and articulation was performed when the age of the patient reached at least 36 months. Cleft-related characteristics and surgical factors affecting the speech outcomes were investigated. Results The ADM was applied in 57 patients with a mean follow-up of45.76 months (SD, 10.69), while no ADM was used in 55 patients with a mean follow-up of 48.43 months (SD, 14.98). Regarding the hypernasality outcome, 33.3% (19 of 57 patients) of the ADM group and 27.3% (15 of 55 patients) of the control group showed a greater than mild-to-moderate degree. The distribution of hypernasality and articulation grade showed no significant difference between the two groups. After controlling for potential risk factors that may affect the speech outcomes, the use of ADM showed no significant relationship with velopharyngeal insufficiency. Conclusion The use of ADM use in primary palatoplasty with radical intravelar veloplasty is not associated with the alteration of speech function in early childhood.