Background: Osteonecrosis of the femoral head (ONFH) is a rare disease requiring joint replacement even in young patients due to progressive femoral head collapse. Regenerative medicine is considered the next treatment of interest to prevent collapse. Methods: We percutaneously administered gelatin hydrogel containing 800-µg recombinant human fibroblast growth factor-2 (rhFGF-2) [TRION] to 64 patients with nontraumatic, precollapse, and large ONFHs. Using the endpoint of radiological collapse, we analyzed the joint-preservation period of the historical control comprising patients with nonsurgically treated ONFH. The primary outcome was an expected collapse rate <35% (joint-preservation rate ≥ 65%) at 24 months after rhFGF-2 treatment. We compared the joint-preservation duration with that of an exactly matched historical control (1:1), with radiological collapse as the endpoint. Secondary outcomes were changes in two validated clinical scores (Harris Hip Score [HHS], University of California, Los Angeles [UCLA] score), bone regeneration assessment, and safety. Findings: From 02.17.2016 to 12.07.2016, 64 patients underwent rhFGF-2 treatment. Of the 63 eligible patients, 7 discontinued the trial and were analyzed as worsened cases. The collapse rate was 42 ·9% at 24 months posttreatment. Under the exact matching analyses, median joint-preservation time was significantly higher in the rhFGF-2 group (45·8 months) than in the control group (11·1 months), with a hazard ratio of 2·6 (95% CI 1·5–4·5; p = 0·0003). The ONFHs tended to improve with bone regeneration to smaller ONFHs, according to the postoperative images. The postoperative clinical scores significantly improved, with an increase of 0·15/month for HHS (95% CI 0·03–0·29; p = 0·008) and 0·06/month for UCLA score (95% CI 0·04–0·08; p < 0·0001). 13 serious adverse events were recorded, these cases showed recovery. Interpretation: Our study suggests that rhFGF-2 treatment increases joint-preservation time with clinical efficacy, radiological bone regeneration, and safety. Clinical Trial Registration Details: University Hospital Medical Information Network clinical trials registry (number, UMI20340). Funding Information: Japan Agency for Medical Research and Development. Declaration of Interests: This investigator-initiated trial was supported by competitive grants from the Japan Agency for Medical Research and Development. rhFGF-2 was provided by Kaken Pharmaceutical Co. (Tokyo, Japan). The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. Ethics Approval Statement: Conducted in accordance with the latest regulatory requirements, including the Declaration of Helsinki and the International Council for Harmonisation - Good Clinical Practice regulations. Approved by the institutional review board or ethics committee of each hospital (Approval number, K023). All patients in TRION provided written informed consent.