Copyright © 2014 by the Endocrine Society. Context: Statins are effective cholesterol-lowering agents that reduce cardiovascular disease risk but also have pleiotropic effects that may extend to other lipid classes. Objective: The purpose of this article was to investigate, in a post hoc analysis, the dose-dependent effects of rosuvastatin on plasma sphingolipids and phospholipids in men with the metabolic syndrome. Methods: Subjects (n = 12) were studied in a randomized, double-blind, triple-crossover trial of a 5-week treatment period with placebo or rosuvastatin (10 or 40 mg/day) with 2-week washouts between treatments. Plasma sphingolipid profiling was determined by liquid chromatography electrospray ionization-tandem mass spectrometry. Results: Rosuvastatin at 10 mg/d (R10) and 40 mg/d (R40) significantly (all P <.001 unless stated otherwise) lowered plasma cholesterol (-34% and -42% [% change with R10 and with R40, respectively]), low-density lipoprotein cholesterol (-49% and -57%) and triglyceride (-24%, P =.03 and -42%) concentrations. Compared with placebo, R10 and R40 significantly decreased the plasma levels of total sphingolipids including those of ceramide (-33%and -37%), sphingomyelin (-27% and-31%), monohexosylceramide (-40% and-47%), dihexosylceramide (-31% and-34%), and trihexosylceramide (-29% and-31%), and GM3 gangliosides (-29% and-26%), lysophosphatidylcholine (-32% and-37%), alkylphosphatidylcholine (-19% and-19%), phosphatidylcholine (-17% and-19%), alkenylphosphatidylcholine (plasmalogen) (-20% and-22%), alkylphosphatidylethanolamine (-20%, P-.008 and-24%, P =.02), alkenylphosphatidylethanolamine (plasmalogen) (-24%, P =.003 and-23%, P =.007), phosphatidylglycerol (-24%, P =.07,-31%, P =.046), and phosphatidylinositol (-34% and-40%). No significant changes were found with phosphatidylethanolamine and phosphatidylserine. Significant dose effects were found with the majority of the plasma sphingolipids, whereas only phosphatidylcholine, lysophosphatidylcholine, alkylphosphatidylcholine, alkenylphosphatidylcholine (plasmalogen), and phosphatidylinositol had significant dose effects. Similar changes were found with plasma sphingolipids when results were normalized to the total phosphatidylcholine concentration. Conclusions: Rosuvastatin dose-dependently lowers plasma sphingolipids and phospholipids, independent of low-density lipoprotein lowering, in men with the metabolic syndrome.