Dysregulation of human tumor necrosis factor a (TNF-alpha) production has been implicated in a variety of human diseases. Serum level of TNF-alpha is frequently detected in clinical diagnosis of cancer patients. Herein, we present an ultrasensitive photoelectrochemical (PEC) sandwich immunosensor for TNF-alpha detection by utilizing anti-TNF-alpha nanobody (Nb) orientedly immobilized to the CdS and Mn cosensitized TiO2 nanorod arrays electrode. Using highly oriented Nb as receptor molecules and a secondary anti-TNF-alpha nanobody conjugated with ZnS nanoparticles as the signal amplification element, the PEC immunosensor for TNF-alpha was developed by monitoring the changes in the photocurrent intensity of the electrode resulting from immunoreaction. The proposed method has the linear range from 2.0 pg/mL to 200 ng/mL and the detection limit was 1.0 pg/mL. The method also reveals high specificity to detect TNF-alpha, with acceptable intra-assay precision and excellent stability. The results for the detection of ten serum samples from lung cancer patients and normal human have good agreement with the clinical data.