Background: Prediction of negative postoperative outcomes after long-bone fracture treatment may help to optimize patient care. We recently completed the Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures (SPRINT), a large, multicenter trial of reamed and unreamed intramedullary nailing of tibial shaft fractures in 1226 patients. Using the SPRINT data, we conducted an investigation of baseline and surgical factors to determine any associations with an increased risk of adverse events within one year of intramedullary nailing. Methods: Using multivariable logistic regression analysis, we investigated fifteen baseline and surgical factors for any associations with an increased risk of negative outcomes. Results: There was an increased risk of negative events in patients with a high-energy mechanism of injury (odds ratio [OR] = 1.57; 95% confidence interval [CI], 1.05 to 2.35), a stainless steel compared with a titanium nail (OR = 1.52; 95% CI, 1.10 to 2.13), a fracture gap (OR = 2.40; 95% CI, 1.47 to 3.94), and full weight-bearing status after surgery (OR = 1.63; 95% CI, 1.00 to 2.64). There was no increased risk with the use of nonsteroidal anti-inflammatory agents, late or early time to surgery, or smoking status. Open fractures had a higher risk of events among patients treated with reamed nailing (OR = 3.26; 95% CI, 2.01 to 5.28) but not in patients treated with unreamed nailing (OR = 1.50; 95% CI, 0.92 to 2.47). Patients with open fractures who had wound management either without any additional procedures or with delayed primary closure had a decreased risk of events compared with patients who required subsequent, more complex reconstruction (OR = 0.18 [95% CI, 0.09 to 0.35] and 0.29 [95% CI, 0.14 to 0.62], respectively). Conclusions: We identified several baseline fracture and surgical characteristics that may increase the risk of adverse events in patients with tibial shaft fractures. Surgeons should consider the predictors identified in our analysis to inform patients treated for tibial shaft fractures. Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.