BACKGROUND: Recent studies have identified specific subsets of diaphyseal humeral fractures for which functional bracing is less effective. The present study tested the hypothesis that a gap between fracture fragments may be a risk factor (after accounting for other potential risk factors) for fracture instability six weeks after functional bracing of humeral shaft fractures. METHODS: We retrospectively identified seventy-nine adult patients (forty-six men, thirty-three women; forty-two fractures on the right side, thirty-seven fractures on the left), each with an acute, closed, AO type-A2 (oblique, 30°) or type-A3 (transverse, lt;30°) mid-diaphyseal humeral shaft fracture treated nonoperatively at three different level-I trauma centers from June 2004 to August 2011. The gap between the fracture fragments was measured on the first radiographs made after the affected upper extremity was placed in a brace. RESULTS: Sixty-three patients (80%) had documented healing of the fracture. Sixteen patients (20%) had motion at the fracture site and a persistent fracture line shown on radiographs six weeks or more after injury. In multivariable analysis, each millimeter of gap between the main fragments with the patient wearing the brace (odds ratio [OR] = 1.4, 95% confidence interval [CI] = 1.1 to 1.7), smoking (OR = 5.8, 95% CI = 1.4 to 25), and female sex (OR = 5.3, 95% CI = 1.2 to 23) increased the risk of fracture instability six weeks after injury (R2 = 0.38, area under the receiver operating characteristic [ROC] curve = 0.81). CONCLUSIONS: The magnitude of the gap between the fracture fragments is an independent risk factor for fracture instability and the lack of a bridging callus six weeks after a diaphyseal humeral fracture. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.