KEY POINTS Antibiotic use 1,717 participating healthcare facilities representing 319,236 beds and 86,463,894 full hospital days (HD) in 2021 (82% of HD). Overall antibiotic consumption: 282 Defined Daily Doses (DDD)/1,000 HD, with variations by clinical specialty. Two antibiotics—amoxicillin and amoxicillin combined with clavulanic acid—account for more than one-third of the DDDs used in participating facilities, with variations by clinical specialty. Overall antibiotic consumption is lower than in 2020, a year marked by high consumption, against a backdrop of profoundly altered hospital activity (COVID-19). Over a 10-year period, a trend toward lower consumption is observed. Over the 2012–2021 period, the use of certain antibiotics or classes of antibiotics has decreased: particularly fluoroquinolones, glycopeptides, and the amoxicillin/clavulanic acid combination in particular, while the consumption of other antibiotics has increased: the piperacillin-tazobactam combination, third-generation cephalosporins, carbapenems, linezolid, and daptomycin. Overall, the share of broad-spectrum antibiotics and certain antibiotics active against penicillin-resistant staphylococci in total consumption increased over the period. Bacterial Resistance 1,010 participating institutions collaborating with 641 clinical laboratories covering 54% of hospital days in 2021. 66,974 Staphylococcus aureus strains collected, of which 12.3% were methicillin-resistant (MRSA). An overall incidence density (ID) of 0.15 MRSA infections per 1,000 hospital days, with an ID nearly four times higher in intensive care units (0.57). 379,080 Enterobacteriaceae strains collected, of which 7.5% were extended-spectrum beta-lactamase (ESBL) producers. Three bacterial species accounted for more than 90% of ESBL-producing Enterobacteriaceae: Escherichia coli (44%), Klebsiella pneumoniae (33%), and Enterobacter cloacae complex (16%). An ID of 0.52 ESBL-producing Enterobacteriaceae infections per 1,000 hospital days, with an ID six times higher in the ICU (3.15). The MRSA and ESBL-positive E. coli infection rates observed in 2021 were lower than in 2020. Over the 2018–2021 period, the MRSA infection rate has stabilized. For ESBL-positive E. coli, following a 2020 marked by the health crisis, the downward trend in infection rates that began in 2017 appears to be resuming.