Onabotulinum toxin A (OBTXA) is an effective treatment for drooling. Our objective was to determine if there are histologic changes in the submandibular glands (SMGs) after repetitive OBTXA injections. The study included blinded histologic analysis and comparison of SMGs with ≥4 OBTXA injections versus controls who never received OBTXA. The number of acinar cells were counted, and the morphology of the cells was evaluated within each histologic sample of the SMGs. Thirty-one glands were analyzed (14 control, 17 cases). No physical differences were observed between the 2 acinar cell groups. There was no significant difference in the number acinar cells per surface area in the control group as compared with the OBTXA group (1.29 ± 0.13 vs 1.17 ± 0.11 cells/μm2, respectively). To conclude, no significant histologic findings were established in this first human study on SMGs post-OBTXA treatment.