In response to various cellular stresses, the cyclin-dependent kinase inhibitor p21 transiently halts cell cycle progression until the stress is resolved, or indefinitely when permanently damaged cells undergo cellular senescence. p21 does so by repressing the transcription of E2F target genes through hypophosphorylation of Rb, but whether regulation of Rb-mediated gene transcription by p21 controls stress responses beyond cell cycle regulation is unknown. Here we report that in concert with arresting cell growth, a p21-responsive Rb pool interacts with specific Stat and Smad transcription factors at select gene promoters to establish a bioactive secretome, referred to as the p21-activated secretory phenotype (PASP). The PASP consists of several hundred secreted factors that continued to be expressed in a p21-dependent fashion after transiently arrested cells have become senescent. We found that the PASP places stressed cells under immunosurveillance, a property that largely depended on a single factor, the macrophage attractant Cxcl14. In mice, hepatocytes promptly attracted macrophages upon induction of p21 and were eliminated after sequential recruitment of B and T cells several days later. Cells normalizing p21 expression within several days after its induction resumed proliferation and were released from immunosurveillance. Collectively, these findings demonstrate that stressed cells are simultaneously placed under both proliferative arrest and immunosurveillance (to prevent the expansion of stressed, potentially damaged cells), and that p21 coordinates these cell-autonomous and non-autonomous activities at the transcriptional level through regulation of Rb. Overall design: RNA-sequencing analyses on cells induced by gamma-irradiation after 2 days (D2) or 4 days (D4) as well as proliferating cells (D0). D2 irradiated cells were infected with shRNA-containing lentivirus to produce D4 irradiated cells with p21 knockdown, Rb knockdown or scrambled control knockdown (shScr).