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Background Cefpodoxime is a broad spectrum third generation cephalosporin with antibacterial activity similar to parenteral cephalosporins. Active against Gram-negative and -positive bacteria, empirical treatment with cefpodoxime is recommended for a wide range of community-acquired infections. We assessed the efficacy of cefpodoxime for the treatment of upper respiratory tract infections (URTI) in Egyptian adults, and evaluated its safety in daily practice. Methods This prospective, observational, multicentre study recruited adult patients, presenting with acute maxillary sinusitis and tonsilopharyngitis, prescribed 200 mg/day cefpodoxime for 5–10 days by their physicians decision. Effectiveness, defined as the proportion of patients exhibiting a complete recovery of clinical symptoms for acute sinusitis and tonsilopharyngitis, was assessed. Safety was evaluated by measuring the prevalence and severity of adverse events (AEs). Results A total of 1425 adult patients were recruited from 134 centers across Egypt. Significant reductions in URTI-related signs and symptoms were observed in subjects prescribed cefpodoxime for a mean 5.87 ± 1.73 days. An 83.3% cure rate and a 16.2% improvement rate were noted for both acute maxillary sinusitis and tonsilopharyngitis patients. Superior outcomes were observed in patients with acute tonsilopharyngitis compared to the acute maxillary sinusitis cohort (86.3% and 77.4%, respectively; p Conclusions High cure rates for acute maxillary sinusitis and acute tonsilopharyngitis, and a favorable safety and tolerability profile were noted following treatment with cefpodoxime. Thus, cefpodoxime seems to be effective as empirical treatment in adult Egyptian patients with acute UTRIs.