Aldosterone receptor antagonists have been shown in randomized trials to reduce morbidity and mortality in adults with symptomatic systolic heart failure. We studied the effectiveness and safety of spironolactone in adults with newly diagnosed systolic heart failure in clinical practice. We identified all adults with newly diagnosed heart failure, left ventricular ejection fraction of <40%, and no previous spironolactone use from 2006 to 2008 in Kaiser Permanente Northern California. We excluded patients with baseline serum creatinine level of >2.5 mg/dl or a serum potassium level of >5.0 mEq/L. We used Cox regression with time-varying covariates to evaluate the independent association between spironolactone use and death, hospitalization, severe hyperkalemia, and acute kidney injury. Among 2,538 eligible patients with a median follow-up of 2.5 years, 521 patients (22%) initiated spironolactone, which was not associated with risk of hospitalization (adjusted hazard ratio 0.91, 95% confidence interval 0.77 to 1.08) or death (adjusted hazard ratio 0.93, confidence interval 0.60 to 1.44). Crude rates of severe hyperkalemia and acute kidney injury during spironolactone use were similar to that seen in clinical trials. Spironolactone was independently associated with a 3.5-fold increased risk of hyperkalemia but not with acute kidney injury. Within a diverse community-based cohort with incident systolic heart failure, use of spironolactone was not independently associated with risks of hospitalization or death. Our findings suggest that the benefits of spironolactone in clinical practice may be reduced compared with other guideline-recommended medications.