Hypertriglyceridemia is common among patients infected with HIV and often requires treatment with a triglyceride-lowering medication, such as fenofibrate. Studies have shown that fenofibrate has the potential to increase serum creatinine, a phenomenon that seems to occur more in patients with baseline renal dysfunction or who are on medications that can affect renal hemodynamics. HIV-infected individuals are at an increased risk of developing renal problems and may be a target population for fenofibrate-induced increases in serum creatinine. The purpose of this report is to describe a case of an HIV-infected individual who experienced a considerable increase in serum creatinine after initiating fenofibrate, and to highlight this underreported yet important adverse effect. Additionally, we discuss the postulated mechanisms, relevant literature among HIV noninfected individuals, and potential risk factors.