OBJECTIVES: To explore the effectiveness and safety of hyaluronic acid (HA) administration for ankle osteoarthritis (OA), and to investigate the effects of variations in HA regimens on treatment responses. DATA SOURCES: Electronic databases, including PubMed and Scopus, were searched from January 1995 to June 2012. STUDY SELECTION: We included randomized controlled trials (RCTs) or prospective cohort studies that employed intra-articular HA to treat ankle OA. Four RCTs, 1 comparative study, and 4 single-arm prospective studies were identified, comprising 354 participants. DATA EXTRACTION: We determined effect sizes for selected studies by extracting pain scores from ankle OA or visual analog scales before and after HA or reference treatments. Meta-regression was implemented to determine whether outcomes were modified by variations in HA regimens. DATA SYNTHESIS: The pooled effect size of improvement scores from baseline was 2.01 (95% confidence interval [CI], 1.27-2.75), whereas the values of comparisons with reference treatments including saline, exercise, and arthroscopy reduced to 0.85 (95% CI, -0.13 to 1.83). The placebo effect of the injection procedure accounted for 87% of the observed efficacy of HA treatment. The meta-regression indicated that the molecular weight was not associated with the magnitude of pain relief, but increases in total doses and active ingredients administered might result in a better outcome. Conversely, increases in injection volumes might cause a reduction of effect sizes. Regarding the side effects, the use of extremely high molecular weight HA frequently caused early postinjection pain. CONCLUSIONS: Intra-articular HA administration can significantly reduce pain in ankle OA compared with the condition before treatment, and it is likely superior to reference therapy. We recommend using multiple doses with an appropriate injection volume to achieve maximum effectiveness.