Quahog Parasite Unknown (QPX) disease has significantly impacted cultured and wild hard clam, Mercenaria mercenaria, populations in the Northeastern United States and is the first formidable disease issue concerning near market sized clams for the industry. Most of what is known about this protistan infection comes from diagnostic reports of mortality events and some preliminary field investigations. Disease dynamics and details of parasite pathobiology are somewhat of an obscurity. This study fostered a laboratory approach towards the experimental induction of infection to confirm direct transmissibility of the disease and to verify trends, observed in the field, of varied host susceptibility based on hard clam stock origin. Evidence of QPX as a directly infective pathogen was achieved, through the utilization of laboratory maintained QPX isolate cultures, as injection of QPX cells into hard clam tissue resulted in infection and subsequent mortalities in matter of a few months. Laboratory conditions did not promote transmission in a trial that aimed to mimic ‘natural’ methods of infection by the cohabitation of infected adult hard clams, obtained from the field, with naïve seed clams. Histopathology of the adult hard clams, at the end of the cohabitation trial, displayed a significant amount of dead and degrading QPX cells, which suggests that laboratory conditions may have promoted healing and resistance of the host. This study has established an experimental infection method that can be used for future investigations concerning crucial aspects of the QPX/hard clam disease system. Laboratory conditions that led to the healing of field infected animals require more investigations and may promote a better understanding of factors affecting disease development.