A critical issue in transfection or co-transfection experiments is to define the appropriate controls. In most cases, a corresponding empty vector is used as one control. We report a paradoxical effect of empty mammalian expression vectors on different reporters. We have found that different empty vectors can inhibit or stimulate the same reporter In addition, the same vector can have different effects on different reporters. This situation is further complicated by the observation that the effects of a vector on a reporter can vary depending on the cells used