Background <p>Infection represents the second most common factor causing death in uremia, partly owing to immune dysfunction. Soluble B7-H6, a soluble form of cell-surface immunoreceptor B7-H6, is induced under infectious conditions. So far, the levels of circulating soluble B7-H6 in uremia cases have not been examined. </p> Methods <p>In this prospective cohort study, 55 patients undergoing maintenance hemodialysis were recruited from October 2021 to February 2022; 20 healthy volunteers were enrolled. <b>Intervention(s):</b> None. All hemodialysis cases were followed up until death, switched to peritoneal dialysis, transplantation, or confirmed infection.</p> Results <p>Patients were followed up for a mean duration of 331 days. Sixteen hemodialysis cases were diagnosed with infectious diseases, including pneumonia in seven cases, urinary tract infection in four, shingles in two, cutaneous infection in two, and sepsis in one. Compared with healthy controls, serum soluble B7-H6 amounts were markedly elevated in hemodialysis cases with or without infection (<i>P</i> &lt; 0.001). Soluble B7-H6 levels were markedly increased in hemodialysis cases with infection compared to counterparts without infection (<i>P</i> &lt; 0.001). Multivariable Cox proportional hazards model showed that soluble B7-H6 was the significant predictor of infection in hemodialysis patients (hazard ratio 3.308; 95% confidence interval 1.118–9.794; <i>P</i> = 0.031). Patients with high-serum soluble B7-H6 levels had a markedly higher cumulative hazard rate of infection in comparison with the low-serum soluble B7-H6 group (<i>P</i> &lt; 0.05). Finally, soluble B7-H6 levels were positively correlated with neutrophil count (<i>P</i> &lt; 0.05).</p> Conclusions <p>This study first showed that serum soluble B7-H6 is elevated in hemodialysis patients and could be considered a potential predictive factor of infection under such conditions.</p>