The production of Manila clam (Ruditapes philippinarum) is seriously threatened by the protistan parasite Perkinsus olseni. We characterized and compared gene expression of Manila clam haemocytes in response to P. olseni in a time-course (10 h, 24 h, 8 d) controlled laboratory challenge (LC), representing the first step of infection, and in a more complex infection in the wild (WI), using a validated oligo-microarray containing 11,232 transcripts, mostly annotated. Several immune-genes involved in NIK/NF-kappaB signalling, Toll-like receptor signalling and apoptosis were activated at LC-10 h. However, down-regulation of genes encoding lysozyme, histones, cathepsins and heat shock proteins indicated signals of immunodepression, which persisted at LC-24 h, when only down-regulated genes were detected. A rebound of haemocyte activity occurred at LC-8 d as shown by up-regulation of genes involved in cytoskeleton organization and cell survival. The WI study showed a more complex picture, and several immune-relevant processes including cytoskeleton organization, cell survival, apoptosis, encapsulation, cell redox- and lipid-homeostasis were activated, illustrating the main mechanism of host response. Our results provide useful information, including potential biomarkers, to develop strategies for controlling Manila clam perkinsosis.