Although left ventricular (LV) dysfunction occurs not uncommonly in the course of cancer therapy, little is known about its natural history and prognostic impact on patients. To investigate the incidence, predictors, and impact on survival of LV systolic dysfunction and recovery during cancer therapy, we conducted a retrospective cohort observational study over 1 year at the University of Texas MD Anderson Cancer Center. We enrolled patients with a decrease in ejection fraction by echocardiography to <50% while undergoing cancer therapy from January 2009 to December 2009. We collected and analyzed their chart data. Of 7,648 patients with echocardiograms in 2009, 366 (4.8%) had ejection fraction <50% and 104 met study criteria. LV systolic dysfunction was associated with cardiotoxic therapy in 53 patients (51%). Recovery occurred in 57 patients (55%) and was independently predicted by younger age, smaller left atrial volume index, and lower B-type natriuretic peptide. At last follow-up, 69 patients (66%) were dead, and 35 (34%) were alive. There was a 20% advantage in 2-year survival among patients with LV systolic recovery compared with those without (95% confidence interval 4% to 41%, p = 0.02). In this retrospective study, LV systolic dysfunction recovery occurred in over half of the patients, appeared independent of cardiotoxic etiology, and associated with a 20% survival benefit at 2 years. Multivariable predictors of recovery are younger age, a small left atrial volume index, and lower B-type natriuretic peptide.