A rise in community-onset Staphylococcus aureus infections has been observed in European countries. To ascertain secular trends of S. aureus infections in primary healthcare in Denmark, we conducted this register-based study in the North Denmark region, during the period 1997–2008. We identified all skin and mucosa specimens obtained by general practitioners and all prescriptions for the preferred oral anti-staphylococcal antibiotic, dicloxacillin. Repeat observations within a 12-month period were excluded prior to the calculation of age and gender standardised incidence rates per 100,000 person-years. We included 108,758 specimens, of which 42,778 (39%) yielded S. aureus. The annual incidence rate of specimens doubled during the study period, reaching 2,399 in 2008. The overall rate of S. aureus isolates increased 2-fold to a stable rate at about 850, but for isolates from children and for impetigo specimens, the increase was steeper, with a peak in 2002. A total of 156,462 dicloxacillin prescriptions had been redeemed and the annual prescription rate increased 2.5-fold, peaking at 3,714 in 2007. In conclusion, the annual rates of specimens, S. aureus infections and dicloxacillin prescriptions more than doubled in primary healthcare during the 12-year study period. A major impetigo epidemic and calls for antibiotic stewardship with increased utilisation of specimens were contributing factors.