Bacteriophage therapeutic development will clearly benefit from understanding the fundamental dynamics of in vivo phage-bacteria interactions. Such information can inform animal and human trials, and much can be ascertained from human cell-line work. We have developed a human cell-based system using Clostridium difficile, a pernicious hospital pathogen with limited treatment options, and the phage phiCDHS1 that effectively kills this bacterium in liquid culture. The human colon tumorigenic cell line HT-29 was used because it simulates the colon environment where C. difficile infection occurs. Studies on the dynamics of phage-bacteria interactions revealed novel facets of phage biology, showing that phage can reduce C. difficile numbers more effectively in the presence of HT-29 cells than in vitro. Both planktonic and adhered Clostridial cell numbers were successfully reduced. We hypothesise and demonstrate that this observation is due to strong phage adsorption to the HT-29 cells, which likely promotes phage-bacteria interactions. The data also showed that the phage phiCDHS1 was not toxic to HT-29 cells, and phage-mediated bacterial lysis did not cause toxin release and cytotoxic effects. The use of human cell lines to understand phage-bacterial dynamics offers valuable insights into phage biology in vivo, and can provide informative data for human trials.