Objective: This study was conducted to investigate the effects of low-level laser (LLL) doses on human red blood cell volume. The effects of exposure to a diode pump solid state (DPSS) (λ = 405 nm) laser were observed. Background data: The response of human blood to LLL irradiation gives important information about the mechanism of interaction of laser light with living organisms. Materials and methods Blood samples were collected into ethylenediaminetetraacetic acid (EDTA)-containing tubes, and each sample was divided into two equal aliquots, one to serve as control and the other for irradiation. The aliquot was subjected to laser irradiation for 20, 30, 40, or 50 min at a fixed power density of 0.03 W/cm2. Mean cell volume (MCV) and red blood cell (RBC) counts were measured immediately after irradiation using a computerized hemtoanalyzer. Results: Significant decrease in RBC volume (p < 0.05, p < 0.0001, p < 0.0001, and p < 0.05, respectively) was induced with variation in laser doses.The highest response was observed with an exposure time of 40 min. This result was reproduced in RBCs suspended in a buffered NaCl solution. In contrast to this finding, laser-induced RBC volume change was completely abolished by suspending RBCs in a solution containing a higher concentration of EDTA. Conclusions: It was suggested that LLL can reduce RBC volume possibly because of the increased free intracellular Ca+2 concentrations, which activate Ca+2-dependent K+ channels with consequent K+ ion efflux and cell shrinkage.