Virtual work has increasingly gained global popularity in the business community, with virtuality becoming integrated into traditional office work settings. As the essence of virtuality comprises geographic dispersion and information systems (IS) use, the implementation of a wide variety of novel and advanced information technologies (IT)/IS as productivity and communication tools have fueled the trend in which virtual work permeates the modern workplace. Despite the heavy use of advanced IT/IS as an integral part of virtual work, our understanding on identifying the work dynamics between IS-related antecedents and employee work outcomes in virtual work contexts is still limited. Drawing on efficacy theory, this study focuses on two important IS-related antecedents within virtual work contexts—IS support for creativity and effective IS use—and their effects on job satisfaction. Specifically, we examine the mediating effect of effective IS use on the relationship between IS support for creativity and job satisfaction above and beyond the perceived usefulness and IS satisfaction, which have previously been recognized as impactful antecedents for IS-related effectiveness. To test the posited hypotheses, data were collected (N = 504) from an online survey platform. Using multiple mediation analyses, the study results confirm our hypotheses that (1) IS support for creativity is positively related to job satisfaction in virtual work settings; and (2) effective IS use mediates the relationship between IS support for creativity and job satisfaction even after controlling for perceived usefulness and IS satisfaction, which indicates the unique explanatory power of effective IS use for increased job satisfaction in virtual work settings. Implications for theory and practice are discussed.