Abstract Serologic biomarker to predict clinical outcome is needed for immune checkpoint inhibitors (ICIs). We evaluated soluble intercellular adhesion molecules‐1 (sICAM‐1) as a predictor of response to ICIs treatment. Ninety‐five patients with cancer treated with ICI were studied. The serum sICAM‐1 levels of baseline, post two cycle therapy and end of therapy (EOT) were measured by enzyme‐linked immunoassay. We randomly assigned the patients into the primary cohort (n = 47) and validation cohort (n = 48). Serum sICAM‐1 post two cycle (277.7 ± 181.6 ng/mL) and EOT (403.9 ± 218.9 ng/mL) were significantly elevated compared to baseline (244.8 ± 153.8 ng/mL, p = 0.008 and p = 0.004, respectively). Early changes of sICAM‐1 (ΔsICAM‐1), deemed as sICAM‐1 after two cycles minus baseline, were assessed. Following ICI treatments, responders had significantly lower ΔsICAM‐1 compared with nonresponders in the primary cohort (p = 0.040) and the validation cohort (p = 0.026). High ΔsICAM‐1 was strongly associated with inferior progression‐free survival (PFS; (primary cohort: p = 0.001 and validation cohort: p = 0.002) and overall survival (OS; (primary cohort: p