Penetrance and age of onset of ATTRV30M amyloidotic neuropathy varies significantly among different populations. This variability has been attributed to both genetic and environmental modifiers. We studied the effect of genetic background on phenotype in two lines of transgenic mice bearing the same ATTRV30M transgene. Amyloid deposition, transthyretin (TTR), megalin, clusterin and disease markers of endoplasmic reticulum stress, the ubiquitin-proteasome system, apoptosis, and complement activation were assessed with WB and immunohistochemistry in donor and recipient tissue. Our results indicate that genetic background modulates amyloid deposition by influencing TTR handling in recipient tissue and may partly account for the marked variability in penetrance observed in various world populations.