To determine the role of the p75 neurotrophin receptor (p75(NTR)) in sympathetic neuron development, we crossed transgenic mice with mutations in p75(NTR), nerve growth factor (NGF) and neurotrophin-3 (NT-3). Neuron number is normal in sympathetic ganglia of adult p75(NTR-/-) mice. Mice heterozygous for a NGF deletion (NGF(+/-)) have 50% fewer sympathetic neurons. In the absence of p75(NTR) (P75(NTR-/-) NGF(+/-)), however, neuron number is restored to wild-type levels. When NT-3 levels are reduced (p75(NTR-/-) NGF(+/-) NT3(+/-)), neuron number decreases compared to p75(NTR-/-) NGF(+/-) NT3(+/+). Thus, without p75(NTR), NT3 substitutes for NGF, suggesting that p75 alters the neurotrophin specificity of TrkA in vivo.