Objective <p>This study investigates the mediating role of high-sensitivity C-reactive protein (hs-CRP) in the relationship between sleep quality and mental health in first-degree relatives of individuals with schizophrenia.</p> Methods <p>A total of 150 first-degree relatives of schizophrenia patients were recruited for this cross-sectional, observational study. Based on their Pittsburgh Sleep Quality Index (PSQI) scores, participants were divided into two groups: the Good Sleep Quality Group (GSQG, <i>n</i> = 77) and the Poor Sleep Quality Group (PSQG, <i>n</i> = 73).</p> Results <p>In the GSQG, mean arterial pressure (MAP), fasting blood glucose (FBG), uric acid (UA), hs-CRP (<i>P</i> &lt; 0.05), and body mass index (BMI), heart rate (HR) (<i>P</i> &lt; 0.01) were significantly lower than in the PSQG. The number of individuals with abnormal mental health conditions (AMHC) in the GSQG was also significantly lower (<i>P</i> &lt; 0.01) compared to the PSQG. For every 1-point increase in PSQI score, hs-CRP levels significantly increased by 0.177 mg/L (<i>P</i> &lt; 0.001) after adjusting for sex, age, MAP, BMI, HR, FBG, HDL, LDL, triglycerides (TG), UA, smoking, and alcohol consumption. The Positive Symptom Total (PST) score increased significantly by 0.336 (<i>P</i> &lt; 0.01) or 0.337 (<i>P</i> &lt; 0.05) due to the mediating effect of hs-CRP in the crude model, and 0.035 after adjustment for the aforementioned covariates (<i>P</i> &lt; 0.05).</p> Conclusion <p>The findings suggest that hs-CRP may mediate the relationship between poor sleep quality and mental health outcomes in this population.&#xa0;</p>