Outpatient antibiotic use in Belgium is among the highest in Europe. The most common reason for an encounter in out-of-hours (OOH) primary care is an infection. In this study, we assessed all consultations from July 2016 to June 2018 at five OOH services. We described antibiotic prescribing by diagnosis, calculated disease-specific antibiotic prescribing quality indicators’ (APQI) values and critically appraised these APQI. We determined that 111,600 encounters resulted in 26,436 (23.7%) antibiotic prescriptions. The APQI diagnoses (i.e., bronchitis, upper respiratory infection, cystitis, tonsillitis, sinusitis, otitis media, and pneumonia) covered 14,927 (56.7%) antibiotic prescriptions. Erysipelas (1344 (5.1%)) and teeth/gum disease (982 (3.7%)) covered more prescriptions than sinusitis or pneumonia. Over 75% of patients with tonsillitis and over 50% with bronchitis, sinusitis, and otitis media were prescribed an antibiotic. Only for otitis media the choice of antibiotic was near the acceptable range. Over 10% of patients with bronchitis or pneumonia and over 25% of female patients with an acute cystitis received quinolones. The APQI cover the diagnoses for only 57% of all antibiotic prescriptions. As 5.1% and 3.7% of antibiotic prescriptions are made for erysipelas and teeth/gum disease, respectively, we propose to add these indications when assessing antibiotic prescribing quality in OOH primary care.