Ifosfamide is one of the most active agents in testicular cancer, with a single-agent activity of 66% in untreated and 21% in cisplatin-pretreated patients. The antitumor effect is comparable in nonseminoma and seminoma. The 23% complete response (CR) rate in patients not pretreated with cisplatin is lower than for those pretreated with cisplatin. This indicates that ifosfamide is less active than cisplatin, and more active than bleomycin, the vinca alkaloids, and possibly etoposide. Ifosfamide and cisplatin are not cross-resistant, with a 67% response rate for cisplatin in ifosfamide-pretreated patients. In a prospective, randomized trial with 203 patients from 1978 to 1982, no significant survival advantage could be seen for PVB (cisplatin, vinblastine, bleomycin) plus ifosfamide v PVB after a 10-year follow-up. In patients refractory to or progressing with cisplatin treatment, ifosfamide-containing regimens rarely induce either partial responses (PRs) or CR. However, in patients relapsing or progressing after a favorable response to cisplatin-based chemotherapy, ifosfamide seems to potentiate the activity of cisplatin and etoposide therapy with about 30% CRs and 15% to 20% long-term, disease-free survivors. This can be explained by the synergism demonstrated in preclinical trials among these three drugs. Due to this high activity in relapsing patients, the cisplatin-etoposide-ifosfamide combination is currently being investigated as first-line treatment in poor risk testicular cancer patients. The optimal dose and schedule still have to be determined, particularly in the combination with granulocyte-granulocyte-macrophage colony stimulating factors that may allow dose escalation of these drugs. An important result of the 15-year follow-up of ifosamide in first-line treatment is the absence of late organ toxicity and particularly of secondary malignancies (1/331 patients) in this young patient population.