Background <p>Proprotein convertase subtilisin/kexin-type 9 (PCSK9) and soluble low-density lipoprotein receptor (sLDLR) are circulating proteins that down regulate LDLR-mediated uptake of plasma LDL-cholesterol into cells. In healthy individuals, plasma PCSK9 and sLDLR levels correlate with total cholesterol and triglycerides, respectively. Because cancer reprograms lipid metabolism, it may alter both the circulating levels of these proteins and their correlations with total cholesterol and triglycerides. To test this possibility, we measured PCSK9, sLDLR, total cholesterol, and triglycerides in plasma from healthy subjects and patients with colorectal cancer liver metastases (CRLM), classified as early recurrent or non-recurrent after liver resection.</p> Methods <p>Plasma PCSK9 and sLDLR were measured using specific ELISA kits. Total cholesterol and triglycerides were measured by enzymatic colorimetry.</p> Results <p>Compared with healthy subjects, CRLM patients had 4- to 6-fold higher sLDLR levels, regardless of recurrence category or gender (<i>P</i> &lt; 0.0001). sLDLR strongly correlated with triglyceride levels (<i>P</i> &lt; 0.0001). Correlations between PCSK9 and sLDLR, total cholesterol, and triglycerides varied by gender and CRLM category. Low PCSK9 levels were associated with larger tumors in early recurrent CRLM, particularly in women (<i>P</i> &lt; 0.01). In women, total cholesterol above the median predicted poorer 5-year overall survival [HR (95% CI), 1.70 (1.07–2.71); <i>P</i> = 0.0152].</p> Conclusions <p>Elevated plasma sLDLR is a candidate diagnostic biomarker for CRLM. In women with early recurrent CRLM, low plasma PCSK9 may indicate large tumors, whereas elevated plasma total cholesterol is an adverse prognostic biomarker. These findings identify early recurrence and gender as important variables when interpreting the clinical significance of lipid dysregulation in CRLM.</p>