N,N-dimethyl-D-erythro-sphingosine (DMS), an N-methyl derivative of sphingosine, is an inhibitor of protein kinase C (PKC) and sphingosine kinase (SK). In previous reports, DMS-induced intracellular $Ca^{2+}$ increase concentration $([Ca^{2+}]_i)$ was studied in T lymphocytes, monocytes, astrocytes and neuronal cells. In the present study, we studied DMS-induced increase of $[Ca^{2+}]_i$ in HCT116 human colon cancer cells. We found that the DMS-induced increase of $[Ca^{2+}]_i$ in colon cancer cells is composed of $Ca^{2+}$ release from intracellular $Ca^{2+}$ stores and subsequent $Ca^{2+}$ influx. The $Ca^{2+}$ release is not related to modulation of inositol 1,4,5-trisphosphate $(IP_3)$ receptor or ryanodine receptor. On the other hand, the $Ca^{2+}$ influx is mediated largely through $Ca^{2+}$ channels sensitive to verapamil, nifedipine, $Ga^{3+}$, and $La^{3+}$. Furthermore, we found that the response is inhibited by bepridil and $Ni^{2+}$, specific inhibitors of $Na^+-Ca^{2+}$-exchanger, suggesting involvement of $Na^+-Ca^{2+}$ exchanger in the DMS-induced $[Ca^{2+}]_i$ increase in colon cancer cells. This inhibition was also observed in U937 monocytes, but not in 1321N1 astrocytes.