Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a potent cholesterol-lowering strategy. This study examined effects of statins and PCSK9 monoclonal antibodies (mAbs) beyond low-density lipoprotein cholesterol reduction, which are not fully defined. To complement in vivo plasma proteomic data, we used HepG2 human hepatoma cells stably expressing apolipoprotein(a) (LPA). Cells were exposed to escalating doses of atorvastatin for ten days, followed by collection of conditioned media and cell lysates for quantitative mass spectrometric analysis. Proteomic profiling of cell lysates revealed a dose-dependent effect on HMG-CoA reductase and other enzymes within the mevalonate pathway. Analysis of conditioned media demonstrated a strong, dose-dependent induction of procollagen C-endopeptidase enhancer 1 (PCOLCE) and a modest increase in secreted LPA. These findings corroborate clinical observations that statin therapy can modestly elevate circulating lipoprotein(a) [Lp(a)] and is associated with increased plasma PCOLCE levels. The HepG2 data provide evidence for a predominant hepatic origin of this PCOLCE response, representing a novel mechanistic insight into statin-associated proteomic changes.