The aim of this study was to investigate the ability of serrapeptase to reduce postoperative swelling, pain and trismus after third molar surgery. Twenty-four healthy individuals with symmetrically impacted mandibular third molars underwent surgical removal in a prospective, intra-individual, randomized, double-blind, cross-over study. Teeth were removed in 2 sessions by the same surgeon. At each session, one third molar was removed under local anaesthesia via a buccal osteotomy. All patients received a combination of either serrapeptase 5mg or placebo tablets and 1000 mg paracetamol tablets at either the 1st or 2nd operation in accordance with the randomization plan. Cheek thickness, pain and interincisal distance were measured preoperatively, and on the 1st, 2nd, 3rd and 7th postoperative days. Cheek thickness and maximum interincisal distance were measured using calipers. Pain intensity was assessed clinically using a numeric scale. There was a significant reduction in the extent of cheek swelling and pain intensity in the serrapeptase group at the 2nd, 3rd and 7th postoperative days (P<0.05), but no significant difference in mean maximal interincisal distance was found between the 2 groups (P>0.05).