We report the first study of macrolide resistance in respiratory tract pathogens in a Serbian paediatric population. It included 5293 Streptococcus pneumoniae, 4297 Streptococcus pyogenes, 2568 Moraxella catarrhalis and 1998 Haemophilus influenzae isolates derived from the respiratory tract and 110 invasive isolates from children aged up to 18 years during 2004–2009. Over the 6-year period, a significant increase (P < 0·01) in macrolide resistance was found in both S. pneumoniae and S. pyogenes that reached 45% and 19%, respectively, in 2009. In the same period, consumption of macrolides increased continually from 2·46 to 5·8 defined daily dose/1000 inhabitants per day. The increase in macrolide resistance in S. pyogenes correlated with consumption of total macrolide and long-acting macrolides (r = 0·879, P = 0·05 and r = 0·922, P = 0·026, respectively). A similar trend was observed in pneumoccoci, although it did not reach statistical significance. The growing problem of macrolide resistance in pneumococci and S. pyogenes in Serbia requires further vigilant surveillance.