Fabrication of nanoscale biosensors based on nanowires (NWs), nanotubes (NTs), and other nanomaterials has recently attracted enormous attention. In comparison to nanoparticles, 1D NWs and NTs have higher sensitivity because of depletion or accumulation of charge carriers at the surface that is caused by binding of charged biological macromolecules at the surface, and affects the entire cross-sectional conduction pathway. Among all 1D nanomaterials, Si NWs and carbon NTs are the most studied materials as biosensors. Functionalized Si NWs and carbon NTs have been demonstrated for detecting proteins, DNA and DNA sequence variations, and cancer markers. However, the biocompatibility and biodegradability of these nanostructures remain to be studied. For example, carbon NTs injected into human blood vessels might accumulate and occlude capillaries in the human brain, which could cause serious damage or be fatal. Being a key functional material with versatile properties, such as dual semiconducting and piezoelectric properties, ZnO has important applications in optoelectronic devices, sensors, lasers, transducers, and photovoltaic devices. In addition, the morphology and the dopant concentration of ZnO nanostructures can be well controlled by tuning the growth conditions, which further broadens their applications. ZnO nanoparticles are believed to be nontoxic, biosafe, and possibly biocompatible, and have been used in many applications in our daily life, such as drug carriers and cosmetics. However, no literature is available on the biodegradability and biocompatibility of ZnO nanowires or nanobelts, which is crucial for the application of ZnO nanostructure for biosensing. In this paper, we present the first study on biodegradability and biocompatibility of ZnO wires. We have conducted a systematic study on the etching and dissolving behavior of ZnO NWs in various solutions with moderate pH values, including deionized water, ammonia, NaOH solution, and horse blood serum. The result shows that ZnO can be dissolved by deionized water (pH≈ 4.5–5.0), ammonia (pH≈ 7.0–7.1, 8.7–9.0) and NaOH solution (pH≈ 7.0–7.1, 8.7–9.0). The study of the interaction of ZnO wires with horse blood serum shows that the ZnO wires can survive in the fluid for a few hours before they eventually degrade into mineral ions. The results of this study are of great significance. First, biosensors made of ZnO nonmaterial have a certain time to perform a device function. Secondly, once completing the corresponding service, the ZnO wires can eventually dissolve into ions that can be completely absorbed by the body and become part of the nutrition. The biodegradability and biocompatibility of ZnO NWs would allow their use for in vivo biosensing and biodetection. Synthesized by a vapor–solid growth process, the ZnO wires used in our study grew along the [0001] direction with a hexagonal cross section and were of high crystalline quality. We studied the dissolving behavior of ZnO wires in deionized water (pH≈ 4.5–5.0), ammonia (pH≈ 7.0–7.1, 8.7–9.0), NaOH solution (pH≈ 7.0–7.1, 8.7–9.0), horse blood serum solution (pH≈ 7.9–8.2), and pure horse blood serum (pH≈ 8.5). The two kinds of ammonia used in our study were prepared by diluting concentrated ammonia with deionized water. The two kinds of NaOH solution were prepared by dissolving solid NaOH in deionized water, and the horse blood serum solution was prepared by diluting pure horse blood serum with NaOH solution (pH≈ 7.0–7.1) with a volume ratio of 1:10. We adopted two processes to investigate the dissolving behavior of a single ZnO wire in different liquids. To study the dissolving process of ZnO wires in deionized water, ammonia, and NaOH solution, we used Process 1 illustrated in Figure 1a. Individual ZnO NWs were firstly manipulated with a pin and placed on a silicon substrate. After that, a droplet of C O M M U N IC A TI O N S