Background This study investigated the efficacy of ChatGPT-3.5 and ChatGPT-4 in assessing drug safety for patients with kidney diseases, comparing their performance to Micromedex, a well-established drug information source. Despite the perception of non-prescription medications and supplements as safe, risks exist, especially for those with kidney issues. The study's goal was to evaluate ChatGPT's versions for their potential in clinical decision-making regarding kidney disease patients. Method The research involved analyzing 124 common non-prescription medications and supplements using ChatGPT-3.5 and ChatGPT-4 with queries about their safety for people with kidney disease. The AI responses were categorized as “generally safe,” “potentially harmful,” or “unknown toxicity.” Simultaneously, these medications and supplements were assessed in Micromedex using similar categories, allowing for a comparison of the concordance between the two resources. Results Micromedex identified 85 (68.5%) medications as generally safe, 35 (28.2%) as potentially harmful, and 4 (3.2%) of unknown toxicity. ChatGPT-3.5 identified 89 (71.8%) as generally safe, 11 (8.9%) as potentially harmful, and 24 (19.3%) of unknown toxicity. GPT-4 identified 82 (66.1%) as generally safe, 29 (23.4%) as potentially harmful, and 13 (10.5%) of unknown toxicity. The overall agreement between Micromedex and ChatGPT-3.5 was 64.5% and ChatGPT-4 demonstrated a higher agreement at 81.4%. Notably, ChatGPT-3.5's suboptimal performance was primarily influenced by a lower concordance rate among supplements, standing at 60.3%. This discrepancy could be attributed to the limited data on supplements within ChatGPT-3.5, with supplements constituting 80% of medications identified as unknown. Conclusion ChatGPT's capabilities in evaluating the safety of non-prescription drugs and supplements for kidney disease patients are modest compared to established drug information resources. Neither ChatGPT-3.5 nor ChatGPT-4 can be currently recommended as reliable drug information sources for this demographic. The results highlight the need for further improvements in the model's accuracy and reliability in the medical domain.