(1) This study aimed to investigate whether baseline clinical and Positron Emission Tomography/Computed Tomography (bPET)-derived parameters could help predicting early response to the first two cycles of chemotherapy (Deauville Score at interim PET, DS at iPET) in patients with classical Hodgkin lymphoma (cHL) to identify poor responders (DS ≥ 4) who could benefit from first-line treatment intensification at an earlier time point. (2) cHL patients with a bPET and an iPET imaging study in our Centre’s records (2013–2019), no synchronous/metachronous tumors, no major surgical resection of disease prior to bPET, and treated with two cycles of ABVD chemotherapy before iPET were retrospectively included. Baseline International Prognostic Score for HL (IPS) parameters were collected. Each patient’s bPET total metabolic tumor volume (TMTV) and highest tumoral SUVmax were collected. ROC curves and Youden’s index were used to derive the optimal thresholds of TMTV and SUVmax with regard to the DS (≥4). Chi-square or Fisher’s exact test were used for the univariate analysis. A multivariate analysis was then performed using logistic regression. The type I error rate in the hypothesis testing was set to 5%. (3) A total of 146 patients were included. The optimal threshold to predict a DS ≥ 4 was >177 mL for TMTV and >14.7 for SUVmax (AUC of 0.65 and 0.58, respectively). The univariate analysis showed that only TMTV, SUVmax, advanced disease stage, and age were significantly associated with a DS ≥ 4. A multivariate model was finally derived from TMTV, SUVmax, and age, with an AUC of 0.77. (4) A multivariate model with bPET parameters and age at diagnosis was satisfactorily predictive of poor response at iPET after ABVD induction chemotherapy in cHL patients. More studies are needed to validate these results and further implement DS-predictive factors at baseline in order to prevent poor response and intensify therapeutic strategies a-priori when needed.