This study investigates for the first time the influence of four doses of rosuvastatin on total fatty acids (TFA) and free fatty acids (FFA) in human plasma and correlates their changes in concentration with changes in the concentration of other lipids involved in cholesterol homeostasis.This study was a placebo-controlled, randomized, double-blind, crossover experiment. The study used a single group of 16 men and consisted of 5 treatment periods lasting 4 weeks each with placebo and 4 doses of rosuvastatin (5, 10, 20, and 40 mg). Each subject changed 5 medical treatments and received in each new treatment different tablets of rosuvastatin or placebo compared to those taken in previous treatments, in a random order. Between treatment periods there was a wash-out period of 2 weeks, without treatment.Changes in TFA and FFA were significant compared to placebo and between different doses of rosuvastatin. We found a continuous logarithmic decrease in levels of TFA, FFA, low-density lipoprotein (LDL)-cholesterol, total cholesterol, triglycerides, phospholipids, and apolipoprotein B-100, and a continuous increase in levels of high-density lipoprotein (HDL)-cholesterol and apolipoprotein A-1 by increases the dose of rosuvastatin. Analysis of the correlation of TFA and FFA with the main lipids and lipoproteins in cholesterol homeostasis indicated a linear regression with high correlation coefficients and all P-values were less than .05 level.The concentrations of TFA and FFA are significantly influenced by the dose of rosuvastatin. They are strongly correlated with those of other lipids and lipoproteins involved in cholesterol homeostasis. The mechanisms of cholesterol homeostasis regulation are involved in changing the concentrations of TFA and FFA.