Chronic infections caused by Pseudomonas aeruginosa are a recurrent clinical situation where antibiotic treatment fails, exacerbated by hypermutable strains that promote multiple-antimicrobial resistance. The shortage of new antimicrobials has led to the reconsideration of fosfomycin, an old antibiotic, for combination therapy due to its reported effectiveness with other antibiotics. However, P. aeruginosa has a very high mutant frequency for fosfomycin resistance in vitro and in vivo, suggesting an elevated risk of resistance to combined treatments. We analyzed the frequency of mutants resistant to fosfomycin combined with tobramycin, amikacin, imipenem, meropenem, ceftazidime, ciprofloxacin, and colistin using P. aeruginosa PA14 (wild-type, WT) and its hypermutable mutS::MAR2xT7 derivative. Experiments were performed in quintuplicate as described previously, with antibiotic concentrations chosen according to EUCAST clinical breakpoints (fosfomycin at 128 g/ml to avoid plate background, with no significant differences in mutant frequencies at 32, 64, and 128 g/ml). For the WT strain, mutant frequencies for individual antibiotics were very high for fosfomycin, high for imipenem and meropenem, moderate for ceftazidime, and relatively low for ciprofloxacin, tobramycin, and amikacin. Mutant frequencies for most combinations were below the limit of detection (-1 1010) except for imipenem plus fosfomycin (1.1 109). For the hypermutable strain, mutant frequencies were 100- to 1,000-fold higher than WT for individual antibiotics; combinations with tobramycin, amikacin, meropenem, ciprofloxacin, and colistin were below detection, but combinations with ceftazidime or imipenem yielded higher-than-expected mutants (1.0 108 and 1.1 107, respectively, higher than the product of single-antibiotic frequencies). These results suggest that fosfomycin combinations with ceftazidime or imipenem are less appropriate than those with tobramycin or ciprofloxacin in terms of mutant occurrence probability. In chronic infections (e.g., cystic fibrosis) with high bacterial loads (10^7 to 10^9 CFU/ml) and hypermutable strains, the probability of finding such mutants is dangerously high. Antibiotic combinations must be carefully considered to minimize double-resistant strain selection, and further studies on pharmacological activity and resistance emergence are needed.