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To model the relative role of old and newly introduced antibiotics in shaping increased antibiotic use.Grouped data covering nationwide consumption and expenditure for out-of-hospital antibiotics in Greece (1990–1999) were used. The antibiotic formulations were categorized into ‘common old formulations’, ‘old formulations with intermittent sales’, ‘recast formulations’ and ‘new substances’. The effect of each category was investigated based on index and pricing analyses.We estimated a 143% net increase in out-of-hospital antibiotic use during 1990–1999. The increase was 59% when all formulations of antibiotic substances available by 1990 were considered. A rapid turnaround of formulations of old substances was noticed with 669 formulations marketed during the decade. Sixteen new antibiotic substances were first introduced after 1990 and by 1999 they accounted for 34.9% of total out-of-hospital antibiotic expenditures. Three new antibiotics (a macrolide and two cephalosporins) accounted for over 90% of this amount. For all three, other less expensive alternatives were available.In the studied setting, out-of-hospital antibiotic use has been expanding in a highly substance-specific and non-rational fashion that is accelerated by the introduction of new drugs.