BACKGROUND: Medial tibial stress syndrome (MTSS) is a common exercise-induced leg injury among athletes and military personnel. Several treatment options have been described in the literature, but it remains unclear which treatment is most effective. OBJECTIVE: The objective of this systematic review was to assess the effectiveness of any intervention in the treatment of MTSS. STUDY SELECTION: Published or non-published studies, reporting randomized or non-randomized controlled trials of any treatment in subjects with MTSS were eligible for inclusion. Treatments were assessed for effects on pain, time to recovery or global perceived effect. DATA SOURCES: Computerized bibliographic databases (MEDLINE, CENTRAL, EMBASE, CINAHL, PEDro and SPORTDiscus) and trial registries were searched for relevant reports, from their inception to 1 June 2012. Grey literature was searched for additional relevant reports. STUDY APPRAISAL: The Cochrane Risk of Bias Tool was used to appraise study quality of randomized clinical trials (RCTs) whereas the Newcastle Ottawa Scale was used to appraise non-randomized trials. The 'levels of evidence', according to the Oxford Centre for Evidence-Based Medicine, addressed the impact of the assessed trials. Two reviewers independently performed the search for articles, study selection, data extraction and appraised methodological quality. RESULTS: Eleven trials were included in this systematic review. All RCTs revealed a high risk of bias (Level 3 of evidence). Both non-randomized clinical trials were found to be of poor quality (Level 4 of evidence). RCTs, studying the effect of a lower leg brace versus no lower leg brace, and iontophoresis versus phonophoresis, were pooled using a fixed-effects model. No significant differences were found for lower leg braces (standardized mean difference [SMD] -0.06; 95 % CI -0.44 to 0.32, p = 0.76), or iontophoresis (SMD 0.09; 95 % CI -0.50 to 0.68, p = 0.76). Iontophoresis, phonophoresis, ice massage, ultrasound therapy, periosteal pecking and extracorporeal shockwave therapy (ESWT) could be effective in treating MTSS when compared with control (Level 3 to 4 of evidence). Low-energy laser treatment, stretching and strengthening exercises, sports compression stockings, lower leg braces and pulsed electromagnetic fields have not been proven to be effective in treating MTSS (level 3 of evidence). CONCLUSION: None of the studies are sufficiently free from methodological bias to recommend any of the treatments investigated. Of those examined, ESWT appears to have the most promise.