Procalcitonin (PCT) is considered a sensitive and specific diagnostic and prognostic marker of systemic bacterial infection, but its value is questionable in certain clinical conditions, particularly in hemato-oncological patients. We analyzed PCT and C-reactive protein (CRP) levels in 56 patients of a pediatric hematology–oncology unit during 110 consecutive non-infectious febrile episodes related to administration of T-cell antibodies (group A; n = 22), alemtuzumab (monoclonal CD52 antibody, CAMPATH-1H/group B; n = 8), interleukin-2 (IL-2/group C; n = 41), prophylactic donor granulocyte transfusions (group D; n = 9), or to acute graft-versus-host disease (aGvHD/group E; n = 10) and compared the results with 20 episodes of Gram-negative sepsis (group F). In the majority of the non-infectious episodes PCT and CRP increased to serum levels statistically indistinguishable from Gram-negative sepsis. Median peak levels of PCT (normal < 0.5 ng/ml)/CRP (normal < 8 mg/l) for groups A–F were 4.34/59.0 (A), 10.14/93.5 (B), 1.11/175.0 (C), 1.43/164 (D), 0.96/34.0 (E), and 8.14 ng/ml /126.0 mg/l (F). Highest single levels were observed in groups A and F. PCT and CRP are of limited value as diagnostic markers of sepsis during T-cell-directed immunomodulatory treatment, granulocyte support, or acute GvHD.