We examine how the transcriptome of Prochlorococcus strain NATL2A changes in the presence of a naturally co-occurring heterotroph, Alteromonas macleodii MIT1002. Significant changes in the Prochlorococcus transcriptome were evident within six hours of co-culture, with groups of transcripts changing in different temporal waves. Many transcriptional changes persisted throughout the 48-hour experiment, indicating that the presence of the heterotroph affected a stable shift in Prochlorococcus physiology. These initial transcriptome changes largely correspond to reduced stress conditions within Prochlorococcus, as inferred from decreases in relative abundance for transcripts encoding DNA repair enzymes and many members of the ‘high-light inducible’ family of stress response proteins. Notable changes were also seen in transcripts encoding components of the photosynthetic apparatus (particularly an increase in PSI subunits and chlorophyll synthesis enzymes), ribosomal proteins and biosynthetic enzymes. Changes in secretion-related proteins and transporters also highlight the potential for metabolic exchange between the two strains. At each of 7 timepoints, samples from 3 biological replicate co-cultures are compared to 3 biological replicate axenic Prochlorococcus cultures that serve as a control.