The aim of this study was to investigate the association between decreased use of macrolides and resistance of common respiratory pathogens in Slovenia from 1999 to 2004. Over a 6-year period the consumption of macrolides in Slovenia decreased by 21.3%, from 3.81 defined daily doses/1000 inhabitants per day (DID) to 3.0 DID. The use of short-acting, intermediate-acting and long-acting subclasses of macrolides decreased by 50%, 18% and 13%, respectively. In the same period, resistance of invasive strains of Streptococcus pneumoniae increased from 4.6% to 11.1% and resistance of non-invasive strains of S. pneumoniae and Streptococcus pyogenes increased from 12.8% to 20.2% and from 7.4% to 12.5%, respectively. Resistance increased significantly more in children than in adults (P=0.05) and was significantly correlated with increased use of intermediate-acting macrolides (r=0.94 for non-invasive S. pneumoniae and r=0.96 for S. pyogenes) in children. Resistance of Haemophilus influenzae and Moraxella catarrhalis was low and did not change. In children and adults, the emergence and spread of multidrug-resistant strains of invasive S. pneumoniae was observed. The decline in total macrolide use was not paralleled by reduced macrolide resistance rates of S. pyogenes and S. pneumoniae during the 6-year period. There was a strong correlation between the use of intermediate-acting macrolides and macrolide resistance of S. pyogenes and S. pneumoniae in children. Further reduction in the use of intermediate- and long-acting macrolides should be encouraged.