Recent advances in radio frequency (RF) sensor systems provide new opportunities to wirelessly collect data from inside the body. “Smart implants” instrumented with sensors have been used as research tools for decades, but only recently have implantable sensors become small enough and robust enough to be used in daily clinical practice. In orthopedic surgery, implants provide a vehicle onto which small RF sensors can be mounted to gather data for diagnostics. However, the sensors must function in a challenging environment which requires long term functionality under demanding physical and mechanical conditions. The purpose of this study was to parametrically test low frequency RF systems under simulated in vivo conditions to determine feasibility of sensor integration into orthopedic applications. Three low frequency RF systems were tested in several clinically relevant scenarios in vitro to characterize (1) strategies for maximizing communication range, (2) physical robustness, and (3) mechanical performance. Systems were tested in air, saline, soft tissue, bone, and in proximity to metal. Hermeticity was assessed during a 208 week period. Effects of γ-irradiation and repeated steam sterilized were measured. Strain at failure was measured by mechanical testing of various packaging configurations. All systems were capable of greater than 20 cm read range under ideal conditions. Saline, soft tissue, and bone had minimal effect on signal transmission, but read range was sensitive to the proximity of stainless steel. The electronics were tolerant of steam sterilization but not of γ-irradiation. Polymer encapsulation is robust enough for many orthopedic applications, but ceramic encapsulated sensors need to be optimized for weight-bearing applications to avoid brittle failure. Although sensor packaging remains a challenge, the technology exists to incorporate passive wireless implantable sensors into orthopedic daily practice.