The development and maintenance of spiral ganglion neurons (SGNs) appears to be supported by both neural activity and neurotrophins. Removal of this support leads to their gradual degeneration. Here, we examined whether the exogenous delivery of the neurotrophin brain-derived neurotrophic factor (BDNF) in concert with electrical stimulation (ES) provides a greater protective effect than delivery of BDNF alone in vivo. The left cochlea of profoundly deafened guinea pigs was implanted with an electrode array and drug-delivery system. BDNF or artificial perilymph (AP) was delivered continuously for 28 days. ES induced neural activity in two cohorts (BDNF/ES and AP/ES), and control animals received BDNF or AP without ES (BDNF/– and AP/–). The right cochleae of the animals served as deafened untreated controls. Electrically evoked auditory brainstem responses (EABRs) were recorded immediately following surgery and at completion of the drug-delivery period. AP/ES and AP/– cohorts showed an increase in EABR threshold over the implantation period, whereas both BDNF cohorts exhibited a reduction in threshold (P < 0.001, t-test). Changes in neural sensitivity were complemented by significant differences in both SGN survival and soma area. BDNF cohorts demonstrated a significant trophic or survival advantage and larger soma area compared with AP-treated and deafened control cochleae; this advantage was greatest in the base of the cochlea. ES significantly enhanced the survival effects of BDNF throughout the majority of the cochlea (P < 0.05, Bonferroni's t-test), although there was no evidence of trophic support provided by ES alone. Cotreatment of SGNs with BDNF and ES provides a substantial functional and trophic advantage; this treatment may have important implications for neural prostheses. J. Comp. Neurol. 486:145–158, 2005. © 2005 Wiley-Liss, Inc.