Background: In just a few years, cardiac resynchronization therapy (CRT) has emerged as a key player in the treatment of advanced heart failure (HF). However, approximately 30% of patients with CRT device implantation do not achieve a favorable response. The purpose of the present study was to identify clinical, electrocardiographic, and echocardiographic predictors of a positive response to biventricular pacing in patients with advanced decompensated HF. Methods: This prospective, observational study involved 42 consecutive patients admitted in emergency settings in our clinic with HF in New York Heart Association (NYHA) functional class III/IV, with QRS duration ≥120 ms and left ventricle ejection fraction (LVEF) ≤35%, who underwent cardiac resynchronization therapy (CRT-P or CRT-D) between January 2010 and July 2014. Statistical analysis was performed using IBM SPSS statistical software. Results: The clinical response (improvement in NYHA class) was recorded in 6 patients (14.3%), while echocardiographic response (change in ejection fraction and/or in end systolic or end-diastolic volumes) was recorded in 10 patients (23.8%). The most frequently observed type of response to CRT was the double (clinical plus echocardiographic) response, recorded in 23 out of 42 patients (54.8%). ROC analysis identified the absence of chronic renal disease and the duration from onset of symptoms to CRT implantation as good predictors for clinical improvement after CRT (AUC = 0.625, 95% CI: 0.400–0.850 for absence of renal failure and AUC = 0.516, 95% CI: 0.369–0.853 for symptoms duration). However, gender, age, duration from symptom onset, and comorbidities were not good predictors for the echocardiographic response (AUC <0.600). Conclusions: CRT represents an important therapeutic option for selected patents with advanced decompensated HF and prolonged QRS interval; however, only some of the commonly used criteria can predict a favorable outcome in patients undergoing CRT.