Based on preclinical studies, the authors undertook a pilot study to determine the hematologic and biologic effects of pretreatment with dexamethasone (Dex) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients receiving carboplatin and ifosfamide. Patients (n = 28) with metastatic solid tumors were randomized to receive pretreatment with Dex or GM-CSF or no pretreatment prior to courses 1 or 2 of carboplatin and ifosfamide. No alteration in dose of chemotherapy was allowed between course 1 and 2. Alterations of hematologic and nonhematologic toxicity and selected biologic parameters were compared between courses 1 and 2. Patients without any pretreatment demonstrated worsening hematologic toxicity in course 2 compared to course 1. In contrast, Dex pretreatment reduced hematopoietic toxicity and improved the absolute granulocyte count (AGC) and platelet count recovery times. For example, course 1 versus course 2 (with Dex pretreatment): AGC nadir (mm3) 153 versus 549 (p = 0.07), days AGC <500/mm3 7.8 versus 4.0 (p = 0.10), days to AGC recovery >1,500/mm3, 26 versus 22 (p = 0.034). Overall comparison between all five cohorts by analyses of variance demonstrated that intervention with Dex improved multiple hematopoietic toxicities, including AGC nadir (p = 0.015), and recovery times to AGC >1,500/mm3 (p = 0.07) and platelet count to >100,000/mm3 (p = 0.05). GM-CSF pretreatment did not worsen hematopoietic parameters after course 2 compared to course 1. Expected biologic effects of Dex and GM-CSF treatment were observed. Patients demonstrated an overall response rate of 32%, 1 complete response, and 8 partial responses. In patients with cancer, pretreatment with Dex or GM-CSF may significantly decrease the hematopoietic toxicity of chemotherapeutic agents.