Objective <p>Cell division cycle 42 (CDC42) regulates prostate cancer growth and metastasis. This study aimed to evaluate the change in serum CDC42 during treatment and its association with the clinical features and prognosis in abiraterone plus prednisone treated metastatic castration-resistant prostate cancer (mCRPC) patients.</p> Methods <p>Seventy-two mCRPC patients who underwent abiraterone plus prednisone therapy were included in this retrospective study, followed by the serum CDC42 level determination at baseline and month 2 (M2). Additionally, serum CDC42 was detected in thirty age-matched healthy controls (HCs).</p> Results <p>The CDC42 level was higher in mCRPC patients versus HCs [median (interquartile range): 1012.5 (655.8–1671.3) versus 606.0 (392.0–1007.0) pg/mL] (<i>P</i> &lt; 0.001). Meanwhile, the CDC42 level was associated with lymph node metastasis (<i>P</i> = 0.041) and visceral metastasis (<i>P</i> = 0.005), but not other clinical characteristics (<i>P</i> &gt; 0.050) in mCRPC patients. Additionally, the CDC42 level was decreased after 2-month treatment (<i>P</i> &lt; 0.001). Inspiringly, shorter radiographic progression-free survival (rPFS) was observed in mCRPC patients with CDC42 &gt; 1000&#xa0;pg/mL than in those with CDC42 ≤ 1000&#xa0;pg/mL at baseline (<i>P</i> = 0.035). Furthermore, shorter rPFS (<i>P</i> = 0.002) and overall survival (<i>P</i> = 0.043) were discovered in mCRPC patients with CDC42 &gt; 1000&#xa0;pg/mL than in those with CDC42 ≤ 1000&#xa0;pg/mL at M2. More importantly, CDC42 at M2 (&gt; 1000 vs. ≤ 1000&#xa0;pg/mL) was independently associated with shorter rPFS in mCRPC patients (<i>P</i> = 0.035, hazard ratio = 2.203).</p> Conclusion <p>The serum CDC42 level associates with LNM, visceral metastasis, and worse prognosis in mCRPC patients underwent abiraterone plus prednisone therapy. However, future prospective, large-scale, and controlled studies are needed for validation.</p>