Background and objectives <p>The role of pretreatment serum α-hydroxybutyrate dehydrogenase (α-HBDH) in small cell lung cancer (SCLC) prognosis prediction remains unknown. We sought to investigate the influence of pretreatment α-HBDH level on the survival of patients with SCLC.</p> Methods <p>The serum concentration of α-HBDH was measured in 400 SCLC patients. The correlations between pretreatment serum α-HBDH concentration and clinicopathological characteristics were analysed. Univariate and multivariate Cox regression analyses were used to evaluate the relationships between α-HBDH levels and the progression-free survival (PFS) and overall survival (OS) of SCLC patients.</p> Results <p>Pretreatment α-HBDH levels were closely associated with tumour stage, NSE levels, LDH levels, and surgical treatment. Patients with high α-HBDH were more likely to have extensive disease, high NSE levels, and high LDH levels (&lt; 250 vs. ≥ 250 U/L, 13.0% vs. 94.8%) and were less likely to have surgery (<i>p</i> &lt; 0.005 for all). Multivariate analysis revealed that tumour stage, tumour size, chemotherapy plus surgery, pretreatment α-HBDH, NSE, and LDH were associated with OS in SCLC patients. Patients in the high α-HBDH group had a 33.9% greater risk of death than patients in the normal α-HBDH group did [HR 1.339; 95% CI: 1.070–1.674]. Patients with high α-HBDH had worse OS than patients with normal α-HBDH did (median OS, 10.0 vs. 15.0 months).</p> Conclusions <p>Elevated pretreatment serum α-HBDH is independently associated with poor OS in SCLC patients. The potential of HBDH as a complementary marker for the prediction of SCLC survival warrants further investigation in conjunction with other indicators.</p>