By using peripheral blood samples from 221 cases of severe acute respiratory syndrome (SARS), 34 of Mycoplasma pneumoniae infection, and 44 healthy adults, we measured the total number of natural killer (NK) and CD158b+ NK cells (CD158b+ NK) using flow cytometric analysis and calculated the percentage of CD158b+ NK cells. The total number of NK and CD158b+ NK cells and the percentage of CD158b+ NK cells were significantly lower in patients with SARS than in those with M. pneumoniae infection (P < .05 for all) and healthy subjects (P < .01, P < .01, P < .05, respectively); in 72 patients with severe SARS than in 149 with mild SARS (P < .05 for all); and in 174 cases of SARS with anti-SARS coronavirus-specific IgG and/or IgM antibodies than in 47 without antibodies (P < .05, P < .01, P < .01, respectively). There were no significant differences for the 3 values among patients with SARS without anti-SARS coronavirus antibody, patients with M. pneumoniae infection, and healthy subjects. The number of NK cells and the expression of CD158b on the surface of NK cells changed in patients with SARS and correlated with disease severity and the presence of anti-SARS coronavirus-specific antibodies; SARS differed from M. pneumoniae infection in pathogenesis involving NK cells. Monitoring the total number of NK and CD158b+ NK cells and the percentage of CDD158b+ NK cells might aid in differentiating SARS from M. pneumoniae infection.