The pro-inflammatory cytokine tumour necrosis factor (TNF) is elevated in abdominal aortic aneurysms (AAA). TNF inhibition dampens AAA expansion in experimental AAA. TNF exists as a membrane-bound (tmTNF) and a soluble form (solTNF). SolTNF primarily activates TNFR1 and induces inflammation and apoptosis, while TNFR2 mainly signals via tmTNF and signals tissue preservation and immune regulation. Non-selective TNF inhibition has successfully treated chronic inflammatory disorders, but has been associated with many adverse effects believed to be caused by blocking the tmTNF-TNFR2 signaling pathway. We hypothezise that selective inhibition of solTNF/TNF-R1 signalling, by XPro1595, will inhibit AAA expansion, but preserve tissue repairing mechanisms and immune regulating functions induced by tmTNF-TNFR2 signalling and thus limit the side effects seen by non-selective anti-TNF therapy, by etanercept (ETN). Nine week old C57BI/6 male mice were anesthetized i.p with xylazine (10 mg/kg) and ketamine (100 mg/kg) and AAA was induced by intraluminal elastase infusion in the infrarenal region of the aorta. Mice were treated i.p. with XPro1595 (20mg/kg), ETN (20 mg/kg) or vehicle twice a week for 14 days. Aneurysm size was measured in vivo as maximal outer abdominal aortic diameter (AD). At termination, AAA tissue was isolated and proteins extracted. Aneurysmal cytokine profile and TNFR1 and TNFR2 levels were determined using multiplex ELISA. Fourteen days after elastase infusion all mice had developed AAA, defined as an increase in AD greater than 50%. In XPro1595 treated mice, AD was significantly lower when compared to vehicle treated mice (117.419.0, vs. 205.5 23.9%, n=8, p=0.01). A similar trend was observed in the ETN treated group, though not significant (130.819.7%, n=9). Both TNF and Interferon (IFN)γ aneurysmal protein levels showed a trend to be elevated in the ETN treated mice when compared to vehicle, this increase were significantly lowered in the XPro1595 treated mice (TNF: 18.1±2.1 vs. 26.78.0, vs 11.61.3 pg/mg, n=5-8, p=0.04); (IFNγ: 2.5±0.4 vs. 3.50.9 vs. 1.30.2 pg/mg, n=7-8, p<0.05). The mean values of aneurysmal interleukin 6 levels displayed a drug dependent decrease, though it did not reach significance (891.8202.7 vs. 681.4±226.8 vs. 318.289.0 pg/mg, n=5-7, p=0.2). Lastly, the aneurysmal protein levels of TNFR1 was reduced by 50% in both ETN and XPro1595- compared to vehicle-treated mice, though only ETN was significantly downregulated (737.9 vs. 323.181.12 vs. 345.9 ± 49.1 pg/mg, n= 6-8, p=0.03). No differences in aneurysmal TNFR2 protein levels were detected; however there were a trend towards elevated TNFR2 in the XPro1595 treated group when compared to ETN (801.3±253.4 vs. 1632±175.6 pg/mg, n=5, p=0.03 by unpaired t-test). In conclusion, selective inhibition of solTNF, by XPro1595, limits AAA expansion.