To evaluate the absolute numbers and frequencies of natural killer T-like (NKT-like) cells in systemic lupus erythematosus (SLE) and to characterize the possible role of the cells. Seventy-nine patients with SLE together with 30 age- and sex-matched healthy controls were enrolled. Flow cytometric determination of peripheral NKT-like cells was carried out for all participants by detecting the absolute counts (Abs) and percentage (%) of CD3 + CD16 + CD56 + cells. Disease activity index, laboratory parameters, and clinical manifestations were collected. The correlation between the cells and these parameters was analyzed. SLE patients had, with respect to controls, considerably decreased values of NKT-like cells (P < 0.001 in both absolute number and percentage). The absolute number of NKT-like cells was found to have positive correlations with WBC, RBC, PLT, C3, C4, IgM and negative correlations with the disease duration, SLEDAI-2K, anti-dsDNA, anti-nucleosome, anti-ribosomal protein, CRP, ESR. Meanwhile, it was found that the percentage values of NKT-like cells decreased in SLE patients with nephritis which was correlated with anti-ribosomal protein and CRP in comparison to SLE patients without nephritis. Moreover, an increase in the NKT-like cell counts was also observed in the patients with a clinical response to the treatment. The absolute counts and frequencies of NKT-like cells decreased in SLE patients significantly, which correlated to disease activities and could recover to normal after the treatment. The NKT-like cells may play an important role in the pathogenesis of SLE and could be a useful marker in the disease assessment. Key Points • The absolute counts and frequencies of NKT-like cells decreased in SLE patients significantly. • NKT-like cells were related to the disease activities and could restore after the treatment. • NKT-like cells may be a useful marker in the disease assessment.