Real-time detection of viral replication inside cells remains a challenge to researchers. The Epic System is a high-throughput, label-free optical detection platform capable of measuring molecular interaction in a biochemical assay, as well as integrated cellular response from measurement of cellular dynamic mass redistribution (DMR) in a cell-based assay. DMR has previously been used to measure cell signaling upon receptor stimulation. In this report, we present the first example of Epic measurement of viral replication-induced cellular response and demonstrate that this system is extremely powerful not only for the sensitive and quantitative detection of viral replication inside cells but also for screening of viral inhibitors. By comparing with conventional assays used for the measurement of viral replication, we show that the Epic response has many advantages including sensitivity, high throughput, real-time quantification and label-free detection. We propose that the Epic system for measurement of integrated cellular response will be an excellent method for elucidating steps in viral replication as well as for the high-throughput screening of inhibitors of rhinovirus and other viruses.