<p>Respiratory tract infections (RTIs) are common in general practice, and represent the main cause of inappropriate antibiotic prescribing, contributing to antimicrobial resistance. This prospective study aims to identify factors associated with inappropriate antibiotic prescribing for RTIs in general practice (GP). The study was conducted in France with the assistance of 15 GP trainees in France, in collaboration with 25 general practitioners. Data were collected from randomly selected GP consultations using ICPC-2 coding, with specific grids for RTI-related visits. Antibiotic prescribing was considered appropriate if it adhered to established guidelines. Of 807 consultations, 173 involved RTIs. Antibiotics were prescribed in 35% of cases, and management was appropriate in 73% of these cases. Sinusitis and bronchitis were more likely to result in inappropriate antibiotic prescriptions. Factors associated with inappropriate prescribing included a light clinical examination (as opposed to systematic), patient considered “at risk”, repeated consultations, and diagnostic uncertainty. Providing a clear diagnostic explanation to patients reduced the risk of inappropriate prescribing. Physicians who received visits from pharmaceutical industry representatives were more likely to prescribe antibiotics inappropriately. This study highlights the complexity of clinical reasoning underlying this practice. Improving the thoroughness of clinical examination, enhancing patient communication, and maintaining independence from pharmaceutical promotion may help optimize antibiotic use. Additionally, rapid diagnostic tests and prescribing software can help reduce uncertainty.</p>