Real-world data are lacking to identify patients with secondary immunodeficiency (SID) who may benefit most from anti-infective interventions. This retrospective analysis used the IQVIA PharMetrics® Plus database to assess baseline characteristics associated with risk of severe infections post-SID diagnosis in patients with hematological malignancies. In 4066 patients included, the mean number of any and severe infections per patient in the one-year pre-SID diagnosis period was 9.5 and 0.7, respectively. Post-SID diagnosis, the mean annualized number of any and severe infections was 19.1 and 1.5, respectively. Receiver operating characteristic curve analysis identified a threshold (cutoff) of three bacterial infections at baseline as optimally predictive of severe infections post-SID diagnosis. Multivariate analysis indicated that hospitalizations, infections (≥3), or antibiotic use pre-SID diagnosis were predictive of severe infections post-SID diagnosis. Evaluation of these risk factors could inform clinical decisions regarding which patients may benefit from prophylactic anti-infective treatment, including immunoglobulin replacement if warranted.