BackgroundSeptic pleuropneumonia is a common cause of morbidity and mortality in horses, but there is limited data available regarding factors associated with survival.Hypothesis/ObjectivesTo identify factors predictive of survival in horses with septic pleuropneumonia.AnimalsA total of 97 horses with septic pleuropneumonia at 2 referral institutions.MethodsA retrospective study was performed. A diagnosis of septic pleuropneumonia was based on the presence of sepsis, pleural effusion, and positive bacterial culture from tracheal aspiration (TA) or pleural fluid (PF).ResultsThirty‐one percent of horses had a recent history of travel. Clinical signs included lethargy (78%), tachycardia (75%), tachypnea (60%), fever (43%), prolonged capillary refill time (22%), and ventral edema (14%). The most common clinicopathologic abnormality was hyperfibrinogenemia (79%). Increased serum creatinine concentration at presentation was negatively associated with survival (OR, 5.13; CI, 1.88–14.01; P = .001) and return to work (OR, 6.46; CI, 1.10–37.92; P = .034). Eighty‐four TA and 67 PF samples were submitted for culture, 98 and 84% of which were positive, respectively. The most common isolate was Streptococcus equi subsp zooepidemicus. Tracheal aspirates were more sensitive than PF for bacterial growth, but some organisms isolated from PF were not isolated from TA. Thoracotomy was positively associated with survival (OR, 0.13; CI, 0.01–0.83; P = .028).Conclusions and Clinical ImportanceIncreased serum creatinine concentration is a negative prognostic indicator and is likely a reflection of dehydration. Submission of TA and PF is recommended. Thoracotomy should be considered as a treatment for pleuropneumonia.