A handling and control system for expandable electrodes (2) of a handpiece wherein a plurality of flexible electrodes (11) made of elastic cables carried by a support assembly are provided with needle-shaped front portions (14-f) that protrude from the support assembly and move in a three-dimensional space under the push of actuators. An electronic control device (27) performs the following functions: a) providing a command to the actuators (17) to perform an initial handling of each cable (14) according to an initial step Δh performing an axial advancement of the front portion (14-f) with respect to the second proximal end (4-b) and a distancing of the front portion (14-f) from the axis H; b) determining for each pair of electrodes (11) the spacing or distance li, measured along a direction perpendicular to the axis (H), between the tips of the front portions (14-f) of the pair of electrodes 11; c) determining a voltage V as a function of the spacing li, V = f(li) and applying to each electrode a pulsed signal having maximum voltage equal to the calculated value V; e) repeating the steps a), b) and c) for a plurality n of steps k successive to the initial one so that the active portions (14-f) of the electrodes move in space in a three-dimensional application area becoming distanced from each other; the voltage applied to the electrodes increases linearly with the increasing of the spacing and is such as to generate an electric field which ensures in said application area the complete electro-poration of the tissue.