Molecules containing the pyrazole nucleus are widely reported as promising candidates to develop new antimicrobial compounds against multidrug resistant (MDR) bacteria no longer inhibited by available antibiotics. Recently, aiming at improving the too high minimum inhibitory concentrations (MICs) of a pyrazole hydrochloride salt (CB1H), CB1H-loaded nanoparticles (CB1H-P7 NPs) were prepared using a potent cationic bactericidal macromolecule (P7) as polymer matrix. Here, CB1H-P7 NPs have been successfully tested on several MDR clinically relevant isolates of Gram-positive and Gram-negative species. CB1H-P7 NPs displayed very low MICs, often 2-fold lower than those of P7 (0.6-4.8 μM vs. 1.2-9.3 μM) [2]. Upon complexation, the antibacterial effects of pristine CB1H were improved by 2-16.4-fold, and, unexpectedly, also the already potent activity shown by P7, when administered alone, was improved by 2-8 times after complexation. Time-killing experiments have established that CB1H-P7 NPs possess rapid bactericidal effects against representative strains of both Gram-positive and Gram-negative species, such as methicillin-resistant Staphylococcus aureus, MDR Pseudomonas aeruginosa, including a colistin-resistant isolate, carbapenemases-producing Escherichia coli and Klebsiella pneumoniae. Selectivity indices up to 2.4, determined by cytotoxicity experiments on human keratinocytes (HaCaT), suggested that CB1H-P7 NPs could be promising for therapeutic uses in the treatment of infections sustained by most isolates, including MDR strains, tested in this study.