Rituximab, a monoclonal antibody against CD20, has achieved great success in the treatment of B cell lymphoma, but many patients have shown resistance to it and led to disease progression eventually. At present, the mechanism of resistance is still not clear, but we consider that it may involve the multiple genes and multiple signaling pathways. Therefore, our study aimed at searching differentially expressed genes of rituximab resistant cell lines (RRCL) by cDNA microarray, and exploring the resistant mechanism of RRCL by using the subsequent bioinformatics methods. In this study, we successfully identified seventy up-regulated genes and forty-two down-regulated genes in both two RRCL. We also isolated the MAPK signaling pathway, which was the significantly enriched pathway in resistant mechanism, through KEGG pathway analysis. Moreover, we discovered the biological behaviors of RRCL that mainly inhibit apoptosis, promote cellular proliferation, transcription and angiogenesis through Gene Ontology (GO) terms analysis. In conclusion, our results suggested that the most closely related pathway to rituximab resistance was MAPK signaling pathway, which may partly be related to its inhibiting the apoptosis of cells and promoting the proliferation of cells and vascular development.