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.