We report a case of serum sickness-like reaction (SSLR) in a 15-month-old boy following oral amoxicillin therapy for an acute otitis media. While symptoms of SSLR improved with a non-steroidal anti-inflammatory (NSAID) and oral corticosteroids, he developed a duodenal ulcer. A nasopharyngeal PCR was positive for Influenza A virus during active disease. A graded challenge to amoxicillin conducted subsequently was negative. It is important to consider infectious causes for SSLR and incorporate proton pump inhibitors if NSAIDs and corticosteroids are used simultaneously to prevent gastric complications. Graded oral challenge to the suspected culprit medication proved to be safe in this case and future large scale studies exploring its role in establishing drug related SSLR in patients are required.