Objectives: To identify knowledge and attitude factors influencing primary care clinician decision-making in diagnosing, managing, and treating urinary tract infections. Design: A qualitative think-aloud study. Methods: Semi-structured qualitative interviews were conducted with primary care clinicians in England over Microsoft Teams. Interviews were transcribed and coded in two ways. First, clinicians’ responses for each scenario were coded as either following (optimal) or not following (suboptimal) evidence-based national guidelines. Second, the knowledge and attitude factors that influenced decision-making were coded according to an empirically-informed umbrella framework. Clinicians external to the study team reviewed the findings to promote their trustworthiness and utility. Setting: English primary care clinicians with the right to prescribe medications in England. Sample: Ten clinicians with prescribing rights in primary care took part. Results: Despite clinicians’ expressing high awareness of relevant evidence-based guidelines (a knowledge factor) and high confidence (an attitude factor), more than half of their decisions were suboptimal in some way. Our framework analysis suggests that knowledge could impede adherence, e.g., where local guidelines conflicted with national guidelines. Conclusions: Suboptimal prescribing decisions could result from a combination of different knowledge and attitude factors. Most clinicians relied on their experiential knowledge rather than using evidence-based guidelines. To optimise antibiotic prescribing, policy-level interventions could increase concordance across local and national guidelines, or more tailored individual-level interventions could help clinicians recognize where their experiential knowledge causes deviations from evidence-based guidelines when diagnosing, treating, and managing urinary tract infections.