Epidemiological studies indicate that exposure to environmental pollutants such as pesticides and dioxins leads to the pathogenesis of lymphoma and leukemia. Here, we show that activation of the aryl hydrocarbon receptor (AhR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in loss of the programmed cell death (apoptosis) response in three different lymphoma cell lines, which plays a key role in the development of cancer, especially lymphoma and leukemia. The AhR-mediated inhibition of apoptosis in vitro was associated with a clear increase of cyclooxygenase-2 (COX-2) and deregulation of genes of the B-cell lymphoma-2 (Bcl-2) family involved in apoptosis including Bcl-xl and Mcl-1 in several lymphoma cell lines. Treatment with the COX-2 inhibitor NS-398 and the AhR antagonist 3′-methoxy-4′-nitroflavone abolished the TCDD-induced resistance of apoptosis in vitro. Furthermore, using micropositron emission tomography imaging, in vivo findings demonstrated that exposure to TCDD promotes the development of lymphoma in superficial lymph nodes of C57BL/10J mice, which was associated with a marked increase of COX-2 expression in the affected lymph nodes. The results indicate that AhR activation and COX-2 overexpression likely represent a mechanism of resistance to apoptosis in lymphoma cell lines that might be relevant for the development of lymphoma in vivo.