We analysed trends in antimicrobial non-susceptibility in methicillin-resistant Staphylococcus aureus (MSRA) from Germany to assess the impact of the changing population structure of MRSA on antimicrobial resistance rates. During two large nationwide multicentre studies in 2004-2005 and 2010-2011, we collected consecutively spa-genotyped MRSA isolates. The increase in non-susceptibility rates for tetracycline and trimethoprim-sulphamethoxazole was associated with the spread of livestock-associated MRSA. A decrease in non-susceptibility rates for aminoglycosides and quinolones affected all major lineages (spa-clonal complexes 003, 008, and 032). All isolated remained susceptible to glycopeptides and linezolid.