Abstract Background Transient swelling is common after lip injections with hyaluronic acid (HA) based fillers. Swelling and other injection‐site reactions may relate to the injection procedure itself, or to gel properties, which differ between fillers due to differences in manufacturing methods. Objectives To evaluate safety and effectiveness of lip injections with two HA fillers manufactured using different gel technologies. Methods In a study sample of 40 subjects, treatment with two soft tissue filler product (HA RK or HA JUS ) was randomly assigned. Subjects were injected with 0.5 cc per upper and lower lip using a standardized injection procedure. Early‐onset adverse events (AEs) were assessed by evaluation up to Day 14. Aesthetic improvement, subject satisfaction, and AEs post‐Day 14 were assessed up to 24 weeks. Results In subjects treated with HA RK , the intensity of early onset swelling, erythema, and pain/tenderness was lower than in subjects treated with HA JUS . Aesthetic improvement was achieved in both groups, and most subjects were satisfied with the appearance of their lips. Treatment‐related AEs post‐Day 14 mostly related to the implant site; most were mild‐to‐moderate, and none were serious. Conclusions The intensity of early‐onset swelling, and other injection‐site reactions was lower in subjects treated with HA RK than in subjects treated with HA JUS . Since both the injection volume and injection procedure were standardized, the difference in local tolerability between the two HA fillers may relate to differences in gel properties. Aesthetic improvement, subject satisfaction, and AE profiles post‐Day 14, however, were similar between filler groups.