Background: It has been noted in observational and interventional studies that individuals exposed to fenofibrate can exhibit a rise in serum creatinine (sCr) concentration. However, it is not known to what extent this phenomenon impacts kidney function in patients who are referred to a nephrology clinic for consultation for chronic kidney disease (CKD). Methods: We conducted a prospective observational study of patients referred to our nephrology clinic for a new evaluation of a rise in sCr or worsening CKD and who were on fenofibrate therapy. We examined the effect of discontinuation of fenofibrate on kidney function, change in sCr, and estimated glomerular filtration (eGFR) at 3, 6, and 12 months. Results: A total of 22 patients (59% women, 86% White, 59% with type 2 diabetes, and 18% with peripheral arterial disease) were captured over 2.5 years. Median sCr at the time of fenofibrate discontinuation was 1.9 (1.1–3.3) mg/dL and eGFR, 32 (17–57) mL/min; proteinuria was absent in 17 (77%). Upon discontinuation of fenofibrate, median sCr decreased to 1.5 (0.9–2.4), 1.4 (1.0–2.5), and 1.4 (1.0–2.3) mg/dL at 3, 6, and 12 months, respectively (p < 0.05); whereas median eGFR increased to 44 (27–71), 45 (23–71), and 42 (21–71) mL/min, respectively (p < 0.05). A ≥30% rise in eGFR was observed in 59% of the patients at 3 months, and it persisted in 45% and 50% of patients at 6 and 12 months, respectively. Conclusion: Discontinuation of fenofibrate in patients referred for CKD evaluation can result in sustained reduction in sCr in about half of the patients and for up to 1 year. There is a need to raise awareness among primary practitioners about this phenomenon. Recognition of fenofibrate as a cause of rise in sCr could reduce unnecessary nephrology consultation and resource utilization.