Anti-phage defence systems in bacterial genomes show great diversity within and between species. We examined whether combinations of defence systems are promoted or antagonised based on the effects of anti-phage protection. By analysing the co-occurrence of defence systems in thousands of Escherichia coli genomes, we found that positive and negative co-occurring combinations are prevalent. Surprisingly, our experimental findings demonstrate that both types of combinations can provide synergistic anti-phage activities, depending on the specific phage being targeted. Furthermore, we observed no consistent patterns of defence system co-occurrence across different bacterial taxa, suggesting that the selection of strains carrying specific combinations of defence systems is driven by environmental pressures rather than mechanistic incompatibilities between defence systems. Additionally, we characterised the synergy between two defence systems that positively cooccurring at the molecular level, revealing the exploitation of similar functional domains among these defence systems. Overall, our study underscores the intricate interplay among antiphage defence systems within a cell.