Novel polymeric systems with antibacterial properties based on medical-grade polyvinyl chloride and antibiotics (Ampicillin, Minocycline, and Rifampicin) in the concentrations up to 1 wt% were prepared by thermoplastic compounding. Thermal stability of the antibiotics was corroborated by IR spectroscopy, X-ray diffraction, differential scanning calorimetry, and H-1 nuclear magnetic resonance spectroscopy. The effect of chemical structure on mechanical properties of the prepared systems was determined by tensile testing measurements and correlated with optical microscopy observations. In vitro antibacterial properties of samples were determined by agar diffusion and adhesion test against Gram-negative and Gram-positive bacteria. Antibiotic release experiments in distilled water and physiological saline solution and follow-up detecting by Ultraviolet-Visible spectroscopy were carried out. A mathematical model was applied to evaluate the release kinetics of the antibiotics from prepared polymeric systems. The results show significant influence of antibiotic's chemical structure on all studied characteristics of the systems due to the various interactions with polyvinyl chloride matrix.