Purpose: The purpose of this study was to obtain information on safety and short-term efficiency of a single intra-articular injection of mannitol-modified cross-linked hyaluronic acid (HANOX-M-XL) in patients with painful first metatarsophalangeal joint osteoarthritis (1stMTPJ-OA). Methods: The study involved an observational, single-arm, prospective multicentre trial, with a 3-month follow-up. Inclusion criteria were patients with symptomatic 1st MTPJ-OA not relieved by analgesics and / or non-steroidal-anti-inflammatory drugs and / or foot orthotic. All patients received a single, imaging-guided intra-articular (IA) injection of 1 mL of HANOX-M-XL in the 1st MTPJ. The primary outcome was the change in pain between the date of injection and month 3. The secondary outcomes were the patient assessment of effectiveness, the decrease in painkiller use and the influence of the radiographic score on the clinical efficacy. Results: Sixty-five participants (72.3% women, mean age = 60) were included in the trial. Coughlin-Shurnas radiological grade was 1 in 28 patients, 2 in 29, and 3 in 6. At baseline and month 3, the average pain (0-10) was 6.5 ± 1.8 and 2.8 ± 2.3, respectively. The change in pain score was highly significant (−3.1 ± 2.9; P < .0001). At baseline there was no statistically difference in pain between the radiological stages ( P = .69). At endpoint, the average pain score was 2.0 ± 1.9 in x-ray stage 1, 3.1 ± 2.3 in stage 2 and 3.3 ± 2.4 in stage 3 ( P = .001). Mild to moderate adverse reactions were reported by 15 patients. All were a transient increase of the hallux pain that occurred immediately and up to 6 hours after injection and resolved in 1 to 7 days. Conclusion: This pilot study suggests that a single IA injection of HANOX-M-XL is safe and mainly benefits patients with mild moderate 1st MTPJ-OA. Further randomized controlled trials are necessary to confirm these preliminary encouraging results.