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Electrochemotherapy (ECT) is an effective antitumor treatment employing locally applied high-voltage electric pulses in combination with chemotherapeutic drugs. For successful ECT, the entire tumor volume needs to be subjected to a sufficiently high local electric field, whereas, in order to prevent damage, the electric field within the healthy tissue has to be as low as possible. To determine the optimum electrical parameters and electrode configuration for the ECT of a subcutaneous tumor, we combined a 3-D finite element numerical tumor model with a genetic optimization algorithm. We calculated and compared the local electric field distributions obtained with different geometrical and electrical parameters and different needle electrode geometries that have been used in research and clinics in past years. Based on this, we established which model parameters had to be taken into account for the optimization of the local electric field distribution and included them in the optimization algorithm. Our results showed that parallel array electrodes are the most suitable for the spherical tumor geometry, because the whole tumor volume is subjected to sufficiently high electric field while requiring the least electric current and causing the least tissue damage. Our algorithm could be a useful tool in the treatment planning of clinical ECT as well as in other electric field mediated therapies, such as gene electrotransfer, transdermal drug delivery, and irreversible tissues ablation.