Context:Medial tibial stress syndrome (MTSS) is a common condition in active individuals and presents as diffuse pain along the posteromedial border of the tibia.Objective:To use cross-sectional, case-control, and cohort studies to identify significant MTSS risk factors.Data Sources:Bibliographic databases (PubMed, Scopus, CINAHL, SPORTDiscus, EMBASE, EBM Reviews, PEDRo), grey literature, electronic search of full text of journals, manual review of reference lists, and automatically executed PubMed MTSS searches were utilized. All searches were conducted between 2011 and 2015.Study Selection:Inclusion criteria were determined a priori and included original research with participants’ pain diffuse, located in the posterior medial tibial region, and activity related.Study Design:Systematic review with meta-analysis.Level of evidence:Level 4.Data Extraction:Titles and abstracts were reviewed to eliminate citations that did not meet the criteria for inclusion. Study characteristics identified a priori were extracted for data analysis. Statistical heterogeneity was examined using the I2 index and Cochran Q test, and a random-effects model was used to calculate the meta-analysis when 2 or more studies examined a risk factor. Two authors independently assessed study quality.Results:Eighty-three articles met the inclusion criteria, and 22 articles included risk factor data. Of the 27 risk factors that were in 2 or more studies, 5 risk factors showed a significant pooled effect and low statistical heterogeneity, including female sex (odds ratio [OR], 2.35; CI, 1.58-3.50), increased weight (standardized mean difference [SMD], 0.24; CI, 0.03-0.45), higher navicular drop (SMD, 0.44; CI, 0.21-0.67), previous running injury (OR, 2.18; CI, 1.00-4.72), and greater hip external rotation with the hip in flexion (SMD, 0.44; CI, 0.23-0.65). The remaining risk factors had a nonsignificant pooled effect or significant pooled effect with high statistical heterogeneity.Conclusion:Female sex, increased weight, higher navicular drop, previous running injury, and greater hip external rotation with the hip in flexion are risk factors for the development of MTSS.