3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most commonly used cholesterol-lowering drugs, with recent clinical trends usually aimed at achieving the lowest possible plasma cholesterol levels. Although the effects of increased plasma cholesterol have been previously reported, it is not obvious how very low plasma cholesterol levels would affect membrane composition and the deformability of red blood cells (RBC). The present study investigated the effects of hypocholesterolemia achieved by atorvastatin therapy on RBC membrane and mechanical properties in guinea pigs fed a normal diet. Two groups of animals were used (atorvastatin-treated, n=12; control n=12), and atorvastatin given orally in isotonic phosphate-buffered saline (PBS) at a dose of 20 mg/kg/day for a 21-day period. Our results indicate that the atorvastatin-treated group had significantly lower plasma total cholesterol (17.42 +/- 1.70 mg/dl), low-density lipoprotein cholesterol (5.25 +/- 2.22 mg/dl) and triglycerides (42.60 +/- 3.78 mg/dl) than the control group (34.08 +/- 1.72, 21.17 +/- 1.41 and 60.64 +/- 2.43 mg/dl, respectively). In addition, membrane cholesterol content was lower (p < 0.0001) and phospholipid content higher (p < 0.0001) in the atorvastatin-treated group, thus decreasing the cholesterol to phospholipid ratio; a significant enhancement in sodium-potassium-ATPase activity also occurred. However, in spite the marked changes of plasma and RBC membrane composition, there was no change of RBC deformability. Note that although our results indicate no adverse rheological alterations, extension of our findings to humans requires caution.