Sepsis and septic shock are major complications of febrile neutropenia (FN) in pediatric patients with cancer (PPCs). The aim of the present study was to determine the association of vitamin D (VD) and cathelicidin levels with sepsis and septic shock in PPCs with FN. A prospective cohort of PPCs with FN who had previously received cytotoxic chemotherapy was analyzed. At baseline, the plasma levels of VD and cathelicidin were quantified. Patients with sepsis and septic shock were compared with patients with FN without complications. Relative risks (RRs) were calculated with 95% confidence intervals (95% CIs) to determine associations. Multiple logistic regression analysis was performed to adjust the results for the identified confounders. A total of 78 episodes of FN were included; 35 (44.8%) completed their FN treatment without complications, 19 (24.4%) presented with sepsis and 24 (30.8%) progressed to septic shock. The median plasma VD level was 15.2 ng/ml, while the median plasma cathelicidin level was 27.9 ng/ml. Patients with severe VD deficiency (RR, 2.34; 95% CI, 1.17-4.70) and patients with cathelicidin levels >41.5 ng/ml (RR, 2.44; 95% CI, 1.07-5.56) exhibited a higher risk of developing sepsis compared with the control group. Patients with severe VD deficiency had a higher risk of septic shock (RR, 1.96; 95% CI, 1.02-3.79) compared with patients without complications, while cathelicidin levels were not associated with septic shock. After adjusting for confounders, cathelicidin levels >41.5 ng/ml (odds ratio, 5.52; 95% CI, 1.17-26.06) remained as an independent risk factor for progressing to sepsis. In patients who developed septic shock, the multivariate model revealed <700 leukocytes/mm3 and glucose levels >100 mg/dl as independent risk factors. In conclusion, higher plasma cathelicidin levels were independently associated with progression to sepsis in PPCs with FN.