Background: Transcatheter tricuspid valve repair (TTVR) is an emerging option for treating high-grade tricuspid regurgitation (TR), mostly performed by edge-to-edge repair, and always guided by transesophageal echocardiography (TOE). In patients with excellent acoustic window, transthoracic echocardiography (TTE) can also provide a comprehensive understanding of tricuspid valve (TV) morphology. Also, in TTVR there is no need for transseptal puncture. Purpose: We sought to determine if edge-to-edge TTVR can be successfully conducted by a novel TTE guiding approach, in conjunction with fluoroscopy. Methods: 30 consecutive patients, scheduled for TTVR, were assigned to a TTE group (n=10), in the presence of excellent acoustic window, and a TOE group (n=20). On top of fluoroscopy, TTVR was guided exclusively by TTE in the first group, with TOE result confirmation solely upon clip release, due to safety reasons. The second group underwent classical TOE guidance. Understanding the 4 right heart chamber views (Fig. 1) and their respective fluoroscopic angulations (Fig.2) was paramount. TR severity, parameters of quality of life and functional capacity were assessed and compared between-groups, at baseline and up to 12 months. Results: Except for lower BMI (TTE 22.3±0.8 vs TOE 29.8±4.3, p<0.001), other baseline characteristics were very similar between groups, e.g., age (81.7±3.9 vs 82.8±4.1, p=0.483) or EuroSCORE II (11.9±10.3 vs 10.4±8, p=0.692). Device success was achieved in all patients, with a total of 15 implanted clips in the TTE group (mean no. of clips / patient 1.5±0.7) and 31 clips in the TOE group (1.5±0.6). Device time (75±37.1 vs 65.7±31.3 minutes, p=0.506) and fluoroscopy duration (16.3±10.5 vs 14.4±7.2 minutes, p=0.564) were also close. TR reduction was successful in all but one patient, in each group (90% vs 95%, p=1.000). TR improvement was equal between-groups, with 2- or more grade reduction in 60% of each group, at 30 days. Thus, grade IV/V and V/V TR, present in 60% of all patients at baseline, dropped to 10% (1/10 vs 2/20, p=1.000) by procedure end and follow-up. No device associated complications occurred. After 12 months, mortality was 13.3%, with one non-cardiac death. At one-year follow-up, all remaining patients had at least one grade reduction in NYHA class (9/9 vs 17/17, p=1.000). Kansas City Cardiomyopathy Questionnaire score and 6-minute walk distance similarly improved (∆24.8±21.4 vs 20.1±13.6 points, p=0.227; ∆93.5±100.4 vs 80.8±64 meters, p=0.121). An in-group difference was also noticed in renal function improvement by follow-up [glomerular filtration rate (GFR) TTE group: 56.8±18.7 to 64.6±14.9 ml/m²/1,73m², p=0.050; TOE group: 50.7±19.9 vs 53.8±20.9, p=0.347]. Conclusion: TTE guidance of TTVR is feasible and safe, provided very good acoustic window. Furthermore, it can offer the same amount of information and be as valuable as TOE. The data encourages screening for a possible TTE guidance approach, even if performed in part with TOE assistance. Such combined imaging guidance could soon make general anesthesia obsolete, which is the main procedural inconvenient in already very sick TTVR patients. The concept of the 4 right-sided chamber views, seen from TTE, TOE, fluoroscopy and CT perspectives, creates a common language between TTVR team members. Successful TR reduction, irrespective of guidance method, led to significant improvement in quality of life after one year.