It has recently been shown that human red blood cells possess a voltage-independent calcium channel which can be influenced by in vitro modification of the membraneous cholesterol content. To determine whether there is also a link between plasma lipids and the calcium influx through this channel under in vivo conditions, the calcium influx was measured in red blood cells from 51 male donors (aged 41 +/- 5 years). The influx through the channel was defined as the nitrendipine (15 mumol/l)-inhibitable part of 45Ca2+ influx. The Ca(2+)-ejecting ATPase was inhibited by vanadate. The results demonstrate a strong inverse relationship (r = -0.81; P < 0.001) between the plasma concentration of high density lipoproteins (HDL) and 45Ca2+ influx. No significant correlation was found between 45Ca2+ influx and triglycerides, low density lipoproteins (LDL), very low density lipoproteins (VLDL), total plasma cholesterol or extracellular electrolytes (K+, Na+, Ca2+, Mg2+). The results indicate that HDL are involved in the modulation of the calcium channel and provide a link between the cellular cholesterol turnover and the calcium influx in the pathogenesis of atherosclerosis and hypertension.