Background Injectable poly‐L‐lactic acid (PLLA) is a synthetic polymer indicated for the correction of facial wrinkles and folds. Animal studies have shown that implantation of PLLA stimulates collagen synthesis; human studies have been limited. Objective To investigate human tissue response to injectable PLLA. Methods and Materials In this exploratory single‐arm, open‐label study, 14 healthy subjects were administered injectable PLLA; punch biopsies at 3, 6, and 12 months were analyzed for qualitative and quantitative changes from baseline in collagen types I and III and assessed for inflammatory responses. Results Quantitative and qualitative increases were observed for collagen types I and III at 3 and 6 months and were statistically significant for collagen type I at 3 and 6 months. Post hoc analyses at 12 months showed nominal collagen increases but were hindered by technical difficulties. The degree of inflammatory response was similar to baseline at 3, 6, and 12 months; all subjects were found to have no or mild inflammation after baseline. Adverse events were mild and among those reported previously. Conclusion Results of this study in humans found statistically significant stimulation of collagen type I with no or mild inflammatory response after administration of injectable PLLA.