Cancer immunotherapy has been shown to enhance established treatment regimens. We evaluated the potential reinforcing effect of IL-15 in trastuzumab treated humanized tumor mice (HTM) which were generated by concurrent transplantation of neonatal NOD-scid IL2R.null mice with human hematopoietic stem cells (HSC) and HER2 positive breast cancer cells (metastasizing SK-BR-3, solid tumor forming BT474). We found that trastuzumab treatment efficacy mainly depends on the immediate anti-tumorigenic cellular effect which is significantly enhanced by tumor interacting immune cells upon cotransplantion of HSC. However, trastuzumab treatment caused elevated CD44 expression on tumor cells that metastasized into the lung and liver but did not hinder tumor cell dissemination into the bone marrow. Moreover, in a number of SK-BR-3-transplanted animals disseminated CD44(high)/CD24(low) tumor cells lost trastuzumab sensitivity. Concerning the FcYRIIIa polymorphism, trastuzumab treatment efficiency in HTM was higher in mice with NK-cells harboring the high affinity FcYRIIIa compared to those with low affinity Fc.RIIIa. In contrast, IL-15 caused the strongest NK-cell activation in heterozygous low affinity Fc.RIIIa animals. Although IL-15 enhanced the trastuzumab mediated tumor defense, an unspecific immune stimulation resulted in preterm animal death due to systemic inflammation. Overall, treatment studies based on "patient-like" HTM revealed critical and adverse immune-related mechanisms which must be managed prior to clinical testing.