CONTEXT: Botulinum A exotoxin is used for various indications, including the treatment of dynamic forehead lines. OBJECTIVE: To determine whether injection with botulinum A exotoxin reconstituted with preservative-containing normal saline (isotonic sodium chloride) is less painful than injection with exotoxin that has been reconstituted with preservative-free saline. DESIGN: Two arms: (1) retrospective study; (2) double-blind, randomized controlled trial. SETTING: A multiple-physician dermatology practice. PATIENTS: (1) Retrospective study-20 consecutive adult patients presenting for treatment of upper-face dynamic lines; (2) prospective study-15 consecutive adult patients presenting for treatment of upper-face dynamic lines. INTERVENTION: In prospective study only, one side (left or right) of the face was treated with exotoxin reconstituted with preservative-containing saline, and the other side, with exotoxin reconstituted with preservative-free saline. MAIN OUTCOME MEASURES: (1) Retrospective study-discomfort at current treatment (with preservative-containing saline) compared with discomfort with most recent prior treatment (with preservative-free saline); (2) prospective study-discomfort on the side treated with preservative-containing saline compared with discomfort on the side treated with preservative-free saline. RESULTS: (1) Retrospective study-18 (90%) of 20 patients reported that treatment with exotoxin reconstituted with preserved saline was less painful than prior treatment with exotoxin reconstituted with preservative-free saline; (2) prospective study-15 (100%) of 15 patients reported less pain in the side of their face treated with exotoxin reconstituted with preservative-containing saline (P<.001). Pain on the preservative-containing side was 54% less. No difference in treatment efficacy between the sides was observed by investigators or patients. CONCLUSION: Use of preservative-containing saline to reconstitute botulinum A exotoxin can significantly decrease patient discomfort on injection.