The primary aim was to identify patient and injury factors independently associated with humeral diaphyseal fracture nonunion after nonoperative management. The secondary aim was to determine the effect of management (operative/nonoperative) on nonunion.From 2008-2017, a total of 734 humeral shaft fractures (732 consecutive skeletally mature patients) were retrospectively identified from a trauma database. Follow-up was available for 663 fractures (662 patients, 90%) that formed the study cohort. Patient and injury characteristics were recorded. There were 523 patients (79%) managed nonoperatively and 139 (21%) managed operatively. Outcome (union/nonunion) was determined from medical records and radiographs.The median age at injury was 57 (range 16-96) years and 54% (n = 359/662) were female. Median follow-up was 5 (1.2-74) months. Nonunion occurred in 22.7% (n = 119/524) of nonoperatively managed injuries. Multivariate analysis demonstrated preinjury nonsteroidal anti-inflammatory drugs (NSAIDs; odds ratio [OR] 20.58, 95% confidence interval [CI] 2.12-199.48; P = .009) and glenohumeral arthritis (OR 2.44, 95% CI 1.03-5.77; P = .043) were independently associated with an increased risk of nonunion. Operative fixation was independently associated with a lower risk of nonunion (2.9%, n = 4/139) compared with nonoperative management (OR for nonoperative/operative management 9.91, 95% CI 3.25-30.23; P < .001). Based on these findings, 5 patients would need to undergo primary operative fixation in order to avoid 1 nonunion.Preinjury NSAIDs and glenohumeral arthritis were independently associated with nonunion following nonoperative management of a humeral diaphyseal fracture. Operative fixation was the independent factor most strongly associated with a lower risk of nonunion. Targeting early operative fixation to at-risk patients may reduce the rate of nonunion and the morbidity associated with delayed definitive management.