Objectives: To evaluate the effects of cardiac resynchronization therapy (CRTd) in patients with type 2 diabetes mellitus (T2DM) optimized via automatic vs. echocardiographic guided approach. Background: Suboptimal optimization of atrio-ventricular (AV) and inter-ventricular (VV) timings reduces CRTd response. Thus, we hypothesize that automatic CRTd optimization could ameliorate clinical outcomes in T2DM patients.Methods: We designed a prospective, multicenter study to recruit, from October 2016 to June 2019, 191 patients with T2DM and heart failure (HF) candidate to receive a CRTd. Study outcomes were CRTd responders rate, hospitalizations for HF worsening, cardiac deaths and all cause of deaths in T2DM patients treated with a CRTd and randomly optimized via automatic (n 93) vs. echocardiographic (n 98) guided approach at 12 months of follow-up.Results: We had a significant difference in CRTd responders rate (68 (73.1%) vs. 58 (59.2%), p 0.038), and hospitalization for HF worsening (12 (16.1%) vs. 22 (22.4%), p 0.030) in automatic vs. echo-guided group of patients. At multivariate Cox regression analysis, automatic guided approach (3.636 [1.271-10.399], CI 95%, p 0.016) and baseline highest values of atrium pressure (automatic SonR values, 2.863 [1.537-6.231], CI 95%, p 0.006) predicted CRTd responders rate. In automatic group, we had significant difference in SonR values comparing CRTd responders vs. non responders (1.24 ± 0.72 g vs. 0.58 ± 0.46 g (follow-up), p 0.001), hospital admission for HF worsening events (0.48 ± 0.29 g vs. 1.18 ± 0.43 g, p 0.001), and cardiac deaths ( 1.13 ± 0.72 g vs. 0.65 ± 0.69 g, p 0.047).Conclusions: automatic optimization increased CRTd responders rate, and reduced hospitalizations for HF worsening. Intriguingly, automatic CRTd and highest baseline values of SonR could predict the outcome of CRTd responders. Notably, there is a significant difference in SonR values for CRTd responders vs. non responders, hospitalizations for HF worsening and cardiac deaths. Clinical trial: ClinicalTrials.gov Identifier NCT04547244;