Prokaryotes carry multiple distinct anti-viral defense systems. However, the impact of carrying a multitude of defense systems on virus resistance remains unclear, especially in a clinical context. Using a collection of antibiotic-resistant clinical strains of Pseudomonas aeruginosa and a broad panel of phages, we demonstrate that intracellular defense systems are major determinants of phage host range and that overall phage resistance scales with the number of defense systems in the bacterial genome. We show that individual defense systems are specific to certain phage types, including Jumbo phages, and that the accumulation of defense systems with distinct specificities results in panphage resistant phenotypes. Accumulation of defense systems is aided by their localization within mobile phage defense elements facilitating horizontal gene transfer. Overall, we show that panphage resistant, defense-accumulating strains of P. aeruginosa with up to 19 phage defense systems already occur in the clinic, which may impact the development of phage-based therapeutics.