The purpose of this study was to examine the feasibility of using irreversible electroporation (IRE) as a non-chemical method for eliminating microorganisms of liquid drugs. The studied drug was a topical ophthalmic medication, a pharmaceutical field in which the problem of microbial contamination has not yet been adequately solved, especially in the case of eye drops prescribed for chronic use. Commercially available Hylo-Comod® preservative-free eye drop solution was subjected to contamination with Escherichia coli bacteria (10⁶ colony forming units/mL). Electroporation parameters for bacterial control were investigated by comparing the effects of electrical fields of 5.4, 7.2, and 10 kV/cm, delivered as 100-µs square pulses at 1 Hz in sequences of 10 pulses, 20 pulses, or 20 pulses delivered as four sets of five pulses with 1-min intervals between each set. Microorganism survival after treatment was determined by pour plate counting. Effects of the treatment parameters on temperature and pH were recorded. Bacterial survival was lowest (0.14% ± 0.03%) after application of 20 pulses delivered as four separate sets. With that application mode, the solution remained at pH 7.5 and the temperature rose to 35.6° ± 0.2°C. Because IRE can be efficiently delivered under conditions that avoid the potentially deleterious effects of electrical pulses on temperature and pH, it appears to be a feasible method for bacterial control of drugs in solution. The principles established in this study can be applied to any drug in solution and optimized individually according to the solution's composition.