Purpose: Mitoxantrone plus prednisone and ixabepilone each have modest activity as second-line chemotherapy in docetaxel-refractory castration-resistant prostate cancer (CRPC) patients. Clinical noncrossresistance was previously observed. Patients and Methods: Metastatic CRPC patients progressing during or after taxane-based chemotherapy enrolled in a phase I multicenter study of ixabepilone and mitoxantrone administered every 21 days along with prednisone. Ixabepilone and mitoxantrone doses were alternately escalated in a standard 3 + 3 design. Patients were evaluated for toxicity and disease response. Dose-limiting toxicities (DLTs) were defined as treatment related, occurring during cycle 1, and included grade 4 prolonged or febrile neutropenia, thrombocytopenia (grade 4 or grade 3 with bleeding), or ≥ grade 3 nonhematologic toxicity. Results: Thirty-six patients were treated; 59% of patients experienced grade 3/4 neutropenia. DLTs included grade 3 diarrhea (n = 1), prolonged grade 4 neutropenia (n = 4), and grade 5 neutropenic infection (n = 1). Due to prolonged neutropenia, the highest dose levels were repeated with pegfilgrastim on day 2 of each cycle. The maximum tolerated dose in combination with pegfilgrastim was not exceeded. The recommended phase II dose is mitoxantrone 12 mg/m2 and ixabepilone 35 mg/m2 every 21 days, pegfilgrastim 6 mg subcutaneously day 2, and continuous prednisone 5 mg twice per day. Thirty-one percent of patients have experienced ≥ 50% prostate-specific antigen (PSA) declines, and two experienced objective responses. Of 21 patients treated with mitoxantrone 12 mg/m2 plus ixabepilone ≥ 30 mg/m2, nine (43%) experienced ≥ 50% PSA declines (95% CI, 22% to 66%). Conclusion: These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.