Objective: Generic medicines provide a safe and economical medical treatment and are used routinely throughout the world. However, a significant proportion of individuals view generic medicines as less safe, less effective and of lower quality compared with their equivalent branded medicines. This study aimed to investigate the effect of an educational intervention on improving perceptions and perceived efficacy of generic medicines. Method: Seventy participants who experienced frequent tension headaches were randomized to receive an educational video about generic medicines or a control video. Participants then alternatively took branded and generic ibuprofen to treat their next two consecutive headaches. Changes in perceptions of generic medicines, pain relief and side effects were measured. Results: The intervention was effective in modifying and improving perceptions of generic medicines in the areas of understanding (p < .05), preference for a generic medicine to treat a serious illness (p < .05), and overall preference for generic medicines (p < .01). However, contrary to predictions, participants in the intervention group reported significantly less pain relief (p = .03) and more symptoms (p = .04) after taking generic ibuprofen compared with branded ibuprofen. Conclusion: This study identified that an educational intervention is effective in modifying and improving perceptions of generic medicines but produced paradoxical effects on drug efficacy and side effects. These findings suggest that complex mechanisms are involved in the relationship between perceptions and drug efficacy and contradict the assumption that improving attitudes toward generic medicines will have a flow-on effect to improving health outcomes.