Objective:To compare the effects of hyaluronic acid (HA) and dextrose prolotherapy (DPT) injections in patients with chronic lateral epicondylalgia (LE). Materials and Methods:Thirty-two patients with at least 6 months of signs and symptoms of LE were randomly allocated into two groups: an HA group (n = 16) and a DPT group (n = 16). HA injection was performed as a single dose of 30 mg/2 mL 1500 kDa high-molecular-weight preparation (baseline). DPT injection was administered with 15% dextrose solution in three doses (baseline, third week, and sixth week). Severity of pain using the visual analog scale score, grip strength with a hand dynamometer, and physical function as determined by the Quick-Disabilities of the Arm, Shoulder, and Hand (Q-DASH) score were determined. Results:DPT was favored over HA for improvements from 0 to 12 weeks for pain with activity (4.81 +/- 1.2 vs. 3.18 +/- 2.3;p = 0.04), pain at night (5.1 +/- 1.9 vs. 4.1 +/- 2.2;p = 0.03), and pain at rest (3.8 +/- 2.09 vs. 2.7 +/- 1.7;p = 0.04). Q-DASH scores improved significantly more from 0 to 12 weeks in the DPT group (43.5 +/- 17.6 vs. 28.4 +/- 13.4;p = 0.04). No between-group improvement was observed for grip pain (7.3 +/- 6.4 vs. 4.8 +/- 3.2;p = 0.38). Conclusions:HA and DPT injections were both effective in reducing pain and increasing grip strength and function in patients with chronic LE. DPT injection was more effective in the short term than HA injection, in terms of pain relief and functional outcome. The study was registered atClinicalTrials.govunder the identifier number NCT04395417.