The management of acute exacerbation of chronic rhinosinusitis (AECRS) is still under debate, especially because there are no adequate studies to support a best-evidence treatment for this condition. Antibiotic use for AECRS has been recommended based on extrapolation of data from acute rhinosinusitis (ARS) or non-placebo-controlled studies. This study aimed to evaluate whether antibiotic therapy modifies the course of AECRS in a randomized, placebo-controlled study. Patients with AECRS were randomized in a double-blinded manner (2:1 ratio) to receive either amoxicillin-clavulanate 875 mg/125 mg twice daily (BID) (AMX-CLAV, n = 21) or placebo capsules (n = 11) during 14 days. All patients were also treated with mometasone furoate and nasal washes with saline. Global sinonasal symptoms (Severity Symptom Assessment [SSA]), quality of life (22-item Sino-Nasal Outcome Test [SNOT-22]), nasal endoscopic score (Lund-Kennedy), and microbiological evaluation were compared to evaluate the efficacy of antibiotic therapy in AECRS. Despite the majority of bacteria cultured from the middle meatus swab were sensitive for AMX-CLAV (84%), both AMX-CLAV and placebo-treated groups presented the same clinical course, with no difference between groups. Both groups exhibited overall improvement of symptoms on day 14 compared to day 0 (p < 0.01), especially the items "nasal secretion" and "nasal obstruction" (p < 0.05). We also observed the same evolution of nasal endoscopic and quality of life scores between placebo and AMX-CLAV. We concluded that AMX-CLAV for 14 days did not change the clinical course of AECRS compared with placebo. The addition of an oral antibiotic to ongoing topical intranasal steroid spray may not provide additional benefit during management of AECRS.