The soluble IL‐6 receptor (sIL‐6R) is generated through either proteolytic shedding of the cognate receptor (PC‐sIL‐6R), or released as the product of differential mRNA splicing (DS‐sIL‐6R). Using monocytic THP‐1 cells, we demonstrate that both mechanisms are independently regulated, and that each process contributes to sIL‐6R production. Shedding of the IL‐6R was activated by the Ca²⁺ ionophore, ionomycin, and inhibited by the TNF‐α protease inhibitor (TAPI). In contrast, basal sIL‐6R release was unaffected by Ca²⁺ depletion and largely insensitive to TAPI. Moreover, although IL‐6R shedding was inactivated by serum starvation, non‐stimulated production remained intact. Basal sIL‐6R production via differential mRNA splicing was shown through the inhibitory action of brefeldin A and an enzyme‐linked immunosorbent assay specific for DS‐sIL‐6R. Release of this isoform was unaffected by ionomycin or TAPI, indicating that Ca²⁺ mobilization activates PC‐sIL‐6R generation, but not DS‐sIL‐6R. The divergent control of these sIL‐6R isoforms indicates that they may independently influence the inflammatory response.