Unique among apes, orangutans (Pongo spp.) develop a chronic respiratory disease called orangutan respiratory disease syndrome (ORDS). The authors define ORDS as intermittent bacterial infection and chronic inflammation of any region or combination of regions of the respiratory tract, including the sinuses, air sacs, cranial bones, airways, and lung parenchyma. Infection in any of these areas can present acutely but then becomes recurrent, chronic, progressive, and ultimately fatal. The closest model to this disease is cystic fibrosis (CF) in people. We hypothesized that use of a 4–8-wk course of combined oral antibiotics used in the treatment of bronchiectasis in CF patients would lead to prolonged symptomatic and computed tomography (CT) scan improvement in orangutans experiencing early signs of ORDS. Nine adult Bornean orangutans (Pongo pygmaeus, eight males, one female, 18–29 yr of age) diagnosed with early ORDS-like respiratory disease underwent CT scan before initiation of treatment. Each animal received a combined course of azithromycin (400 mg 3/wk, mean 7 mg/kg) and levofloxacin (500 mg PO q24h, mean 8.75 mg/kg) for a period of 4–8 wk. CT scan was repeated 6–14 mon after completion of antibiotic treatment. Pretreatment CT showed that six of nine animals had lower respiratory pathology (airway disease, pneumonia, or both). All six orangutans had concurrent sinusitis, mastoiditis, airsacculitis, or a combination of these conditions. Upper respiratory disease alone was observed in three animals. CT showed improvement or resolution in four of five sinusitis cases, improvement in one of two instances of mastoiditis, resolution in five of six instances of airsacculitis, improvement or resolution in six of six instance of lower airway disease (P = 0.03, 95% CI 0.54–1.0], and resolution in five of five cases of pneumonia. Resolution of pretreatment clinical signs was observed in all nine animals. Two developed signs not present at pretreatment. These results show that combination antibiotic therapy with azithromycin and levofloxacin provides improvement in clinical signs and CT evidence of ORDS-related pathology, resulting in symptom-free status in some animals for up to 33 mon.