Background and Objectives: Minimally invasive cardiac surgery (MICS) has been developing since 1996. Peripheral cannulation is required to perform MICS, and good venous drainage and a bloodless field are crucial for the success of this procedure. We assessed the benefits of using a virtually wall-less cannula in comparison with the standard thin-wall cannula in clinical practice. Materials and Methods: Between January 2021 and December 2022, we evaluated 65 elective patients, who underwent isolated minimally invasive mitral valve surgery. Both the virtually wall-less and the thin-wall cannulas were placed through a surgical cut-down. Patients' characteristics at baseline were similar in the two groups, except for the body surface area (BSA), which was greater in the virtually wall-less group compared to the thin-wall one. In the standard group, the size of the cannula was chosen depending on the patient's BSA, and the choice of the Smartcannula was based on their height. Results: There were no significant differences between the two groups in terms of negative pressure applied, target flow achieved, hemolysis, the need for blood transfusion, and the post-operative increases in liver and renal enzymes. However, in all the patients, the estimated target flow was achieved, thereby showing the better hemodynamic performance of the virtually wall-less cannula, since, in this group, the patients' BSA was significantly greater compared to the thin-wall group. Ultimately, the mean cross-clamp time, as an indirect index of the effectiveness of the venous drainage, is shorter in the virtually wall-less group compared with the thin-wall group. Conclusions: The virtually wall-less cannula should be preferred in minimally invasive mitral valve surgery due to its superior performance in terms of venous drainage compared with the standard thin-wall cannula.