<b><i>Background:</i></b> Little is known about the effect of low-density lipoprotein (LDL) cholesterol, triglyceride (TG), and high-density lipoprotein (HDL) cholesterol levels on renal function decline in patients receiving specialized pre-dialysis care. <b><i>Methods:</i></b> In the prospective PREPARE-2 study, incident patients starting pre-dialysis care were included when referred to one of the 25 participating Dutch specialized pre-dialysis outpatient clinics (2004-2011). Clinical and laboratory data were collected every 6 months. A linear mixed model was used to compare renal function decline between patients with LDL cholesterol, TG, or HDL cholesterol levels above and below the target goals (LDL cholesterol: <2.50 mmol/l, TG: <2.25 mmol/l, and HDL cholesterol: ≥1.00 mmol/l). Additionally the HDL/LDL cholesterol ratio was investigated (≥0.4). <b><i>Results:</i></b> In our study population (n = 306), the median age was 69 years and 70% were male. Patients with LDL cholesterol levels above the target of 2.50 mmol/l experienced an accelerated renal function decline compared to patients with levels below the target (crude additional decline: 0.10 ml/min/1.73 m²/month, 95% CI 0.00-0.20; p < 0.05). A similar trend was found for TG levels above the target of 2.25 mmol/l (0.05 ml/min/1.73 m²/month, 95% CI -0.06 to 0.16) and for a HDL/LDL cholesterol ratio below 0.4 (0.06 ml/min/1.73 m²/month, 95% CI -0.05 to 0.18). Adjustment for potential confounders resulted in similar results, and the exclusion of patients who were prescribed lipid-lowering medication (statin, fibrate, or cholesterol absorption inhibitor) resulted in a slightly larger estimated effect. <b><i>Conclusion:</i></b> High levels of LDL cholesterol were associated with an accelerated renal function decline, independent of the prescription of lipid-lowering medication.