Lytically infected EBV‐positive lymphoblastoid cells enhance the growth of early‐passage, but not late‐passage, EBV‐immortalized lymphoblastoid cell lines (LCLs) in SCID mice and have enhanced IL‐6 secretion. Here, we have examined the importance of IL‐6 for the growth of early‐passage LCLs (EPL) in SCID mice, identified lytic EBV proteins that activate IL‐6 production and compared viral and cellular differences between early versus late passage LCLs (LPL). IL‐6 was required for efficient growth of EPL in SCID mice. The EBV immediate‐early (IE) proteins, BRLF1 and BZLF1, each induced IL‐6 secretion when transfected into 293 and BJAB cells. Interestingly, the combination of BZLF1 and the latent EBV protein, LMP‐1, induced much more IL‐6 expression in both 293 and BJAB cells than either protein alone. Both BZLF1 and BRLF1 also enhanced IL‐10 production in 293 cells. In comparison to the EPL, LPL had much reduced expression of early lytic viral proteins and cellular IL‐6. In contrast, expression of cellular IL‐10 was similar in EPL versus LPL, while VEGF secretion was increased in late‐passage LCLs. These results suggest that both BRLF1 and BZLF1 contribute to IL‐6 secretion in lytically infected cells and that lytically infected cells may promote early lymphoproliferative disease in patients through enhanced IL‐6 production. © 2007 Wiley‐Liss, Inc.