The aim of this study was to explore whether botulinum toxin A (BTXA) injection treats epiphora secondary to submandibular gland (SMG) transplantation for severe keratoconjunctivitis sicca. Fifteen patients with epiphora after SMG transplantation were separated to three groups, and received 15 U, 20 U and 25 U BTXA injection in the transplanted SMG, respectively. Secretion of transplanted SMG was assessed subjectively by visual analogue scale (VAS) regarding epiphora, and objectively by Schirmer test. There were no significant differences in the 15-U BTXA group regarding the values of the VAS on epihora before and 1 month after BTXA injection. While in 20-U group and 25-U group, the values of VAS on epihora decreased significantly after BTXA injection, and lasted for 6 months. Under resting conditions, the secretion of transplanted SMG decreased 64.4%, 73.0% and 78.0% in 15-U, 20-U and 25-U groups, respectively (P < 0.01), in 1 month after BTXA injection; significant secretion decreasing lasted 3 months only in the 25-U BTXA group. BTXA injection can decrease the secretion of transplanted SMG significantly, relieving the symptoms of epiphora; 25 U BTXA is a suitable dose to treat `opportunistic epiphora' after SMG transplantation.