The mechanism of lead (Pb2+)-induced neurotoxicity has not yet been fully elucidated. The purpose of this study was to examine the effects of Pb2+ on several protein kinase C (PKC) isoforms and the nuclear factor-κB (NF-κB)–I-κB kinase-alpha (IKK-α) axis in cultured neuronal cells. Neurons were isolated from rat fetal brain at the 18th day of gestation of pregnant Sprague Dawley rats and cultured for 10 days before use. Neurons were exposed to Pb2+ at concentrations of 10−10, 10−9, 10−8, and 10−7 mol/L for 14 h and antigens of typical PKC-α,β,γ novel PKC (ε, δ), atypical PKC (λ), NF-κB (p50), and IKK-κ were enriched by immunoprecipitation and determined by western blotting. Total, calcium-dependent and independent PKC activities were also determined by counting the transferred γ-32 P in the substrate-histone. The results indicated that inorganic Pb2+ significantly reduced all PKC isoforms (α,β,γ, ε, λ) except δ, inhibiting the total, calcium-dependent and calcium-independent PKC activities in a dose-dependent manner. Additionally, Pb2+ gradually reduced NF-κB (p50) and IKK-α protein levels. This suggests that Pb2+ exhibits varying preference for individual PKC isoforms but reduces the NF-κB–IKK-α axis to a similar extent.