The human granulocytic ehrlichiosis agent (HGEa) survives extreme differences between ticks and humans possibly by use of differential expression of specific antigens for survival in different hosts. The role of the immunodominant p44 antigens is unknown. In this study HGEa cultured in human or tick cells was probed with human mouse and hamster serum and with monoclonal antibodies (MAbs). p44 antigens were strongly expressed in human HL-60 cells but were strikingly reduced in tick cells. In HGEa alternately grown in HL-60 or tick cells a p44 epitope recognized by MAb R5E4 was expressed in human but not tick cells. This was not a temperature effect because incubation of infected tick cells at 37°C did not induce expression of the p44 epitope. The p44 antigen predominates in human but not tick cells and may be involved in regulatory changes that mediate survival of the HGEa by immune modulation after tick transmission.