Exercise-induced production of interleukin (IL)-6 results in the expression of chemokine CXC-motif ligand 1 (CXCL1) in mice. Recent studies described the increase in serum IL-6 levels during immersion of subjects in hot water. The present study investigated the effects of a 20-min head-out water immersion in 42 °C water (hot-HOI) on serum concentrations of CXCL1 in eight healthy men. Venous blood samples were taken at rest, immediately after hot-HOI, as well as 1, 2, 3, and 4 h after hot-HOI for measurements of serum concentrations of CXCL1, IL-6, tumor necrosis factor (TNF)-α, high-sensitivity C-reactive protein (hsCRP), while assessing counts of blood cells (CBC) and monitoring core temperature (Tcore). Tcore and serum IL-6 increased during hot-HOI and remained high until 4 h after hot-HOI. However, serum CXCL1, TNF-α, hsCRP, and CBC remained constant throughout the experiment. In conclusion, the results from our study demonstrated that 20-min hot-HOI increased serum IL-6, but not CXCL1 in healthy man.