Organ environment has been shown to modulate the efficacy of chemotherapy. A nude mouse model was used to study the influence of the in vivo environment on the sensitivity to chemotherapy of a human melanoma. A melanoma clone, SB1A, was implanted in two different sites (adrenals and subcutis) of nude mice which were subsequently treated with high-dose cyclophosphamide. After treatment, a 42% complete response rate was observed for the adrenal implants. No response was seen in the subcutis despite the same chemotherapy administration. This result is not attributable to differences in drug concentration in the target sites, because of the high-dose chemotherapy used. This model shows that the in vivo environment modifies the sensitivity to chemotherapy of a malignant melanoma clone. Further research is needed to clarify the role of host factors and of specific cell-stroma interactions that modify the biological behavior of malignant cells.