We examined the role of macrophages in inflammation associated colorectal cancer (CRC). Given the emerging evidence on immune-microbiota interactions in CRC, we also sought to examine the interaction between macrophages and gut microbiota. To induce CRC, male C57BL/6 mice (n=32) received a single injection of azoxymethane (AOM) followed by three cycles of dextran sodium sulfate (DSS) supplemented water at weeks 1, 4, and 7, respectively. Prior to the final DSS cycle (week 7) and twice weekly until sacrifice, mice (n=16/group) received either 200μl i.p. of clodronate filled liposomes (CLD) or phosphate buffered saline (PBS) encapsulated liposomes to deplete macrophages. Colon tissue was analyzed for polyp burden, macrophage markers, transcription factors, and inflammatory mediators. Stool samples were collected and DNA was isolated and subsequently sequenced for 16S rRNA. Clodronate liposomes decreased tumor number by ~36% and specifically large (≥1mm) tumors by ~36% (p<0.05). This was consistent with a decrease in gene expression of EMR1 in the colon tissue and polyp tissue as well as expression of select markers associated with M1 (IL-6) and M2 macrophages (IL-13, IL-10, TGFβ & CCL17) in the colon tissue (p<0.05). Similarly, there was a decrease in STAT3 and MAPK p38 and ERK signaling in colon tissue. Clodronate liposomes increased the relative abundance of the Firmicutes phylum (p<0.05) and specifically Lactobacillaceae and Clostridiaceae families, which have been associated with reduced CRC risk. Overall, these data support the development of therapeutic strategies to target macrophages in CRC and provide support for further evaluation of immune-microbiota interactions in CRC.