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Acute-phase viral infections, such as COVID-19, trigger a complex interplay of proinflammatory and regulatory responses, influencing both tissue repair and damage. Intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and platelet endothelial cell adhesion molecule-1 (PECAM-1) play crucial roles in immune activation, regulation, and homeostasis during infection. This study included adult patients hospitalized at the University Hospital in Cracow, Poland, with confirmed SARS-CoV-2 infection between January and June 2021. Blood samples were collected at three time points and categorized based on the time since symptom onset: first, second, or third week of infection. The objective was to assess serum levels of sICAM-1, sVCAM-1, and sPECAM-1 in relation to in-hospital mortality and key biochemical and clinical parameters. Among 276 patients (63% males) with a median age of 62 years, pneumonia was confirmed in 89% of cases, with an in-hospital mortality rate of 12.7%. Mortality was associated with advanced age (71(9) vs. 61(18) years p<0.001) and comorbidities such as hypertension, diabetes, chronic kidney disease, heart failure, and atrial fibrillation. Non-survivors exhibited significantly lower adhesion molecule levels. Median (IQR) concentrations in non-survivors vs. survivors, respectively, were at first week: sICAM-1: 279(114) vs. 399(328) ng/mL (p<0.001); sVCAM-1: 2944(2760) vs. 4670(3331) ng/mL (p<0.001); sPECAM-1: 15(6) vs. 17(7) ng/mL (p<0.05). Results for third week were: sICAM-1: 271(109) vs. 461(296) ng/mL (p<0.01); sVCAM-1: 1875(2034) vs. 1426(1194) ng/mL (p=0.054); sPECAM-1: 18(7) vs. 25(13) ng/mL (p<0.01). Proportionally, sVCAM-1 was highest at symptoms onset, while sICAM-1 and sPECAM-1 rose later. sICAM-1 positively correlated with interleukin-1α, sVCAM-1 was linked to pneumonia and inflammation, and sPECAM-1 negatively correlated with inflammatory markers and D-dimers. These findings highlight the dynamic role of adhesion molecules in COVID-19 and suggest their potential as biomarkers and therapeutic targets for optimizing treatment strategies.