Fosfomycin is active in vitro against extensively drug-resistant (XDR) and pandrug-resistant (PDR) Pseudomonas aeruginosa and Klebsiella pneumoniae carbapenemase-producing strains; however, the in vivo effectiveness against such pathogens is almost unknown. A multicentre, observational, prospective case-series study was performed in 11 ICUs. All consecutive fosfomycin-treated patients suffering from XDR or PDR fosfomycin-susceptible, microbiologically documented infections were recorded. Clinical and microbiological outcomes were assessed. A safety analysis was performed. In total, 68 patients received fosfomycin during the study period, 48 of whom were considered suitable for effectiveness analysis based on predefined criteria. Bacteraemia and ventilator-associated pneumonia were the main infections. Carbapenemase-producing K. pneumoniae and P. aeruginosa were isolated in 41 and 17 cases, respectively. All isolates exhibited an XDR or PDR profile, being fosfomycin-susceptible by definition. Fosfomycin was administered intravenously at a median dose of 24g/day for a median of 14 days, mainly in combination with colistin or tigecycline. Clinical outcome at Day 14 was successful in 54.2% of patients, whilst failure, indeterminate outcome and superinfection were documented in 33.3%, 6.3% and 6.3%, respectively. All-cause mortality at Day 28 was 37.5%. Bacterial eradication was observed in 56.3% of cases. Fosfomycin resistance developed in three cases. The main adverse event was reversible hypokalaemia. In conclusion, fosfomycin could have a place in the armamentarium against XDR and PDR Gram-negative infections in the critically ill. Resistance development during therapy, which has been a matter of concern in previous studies, did not occur frequently. The necessity of combination with other antibiotics requires further investigation.