Arthritogenic alphaviruses are mosquito-borne viruses characteristically associated with severe rheumatic disease and febrile illness. While this group of arboviruses house significant epidemic potential due to expanding competent vectors, host plasticity, and recombination events increasing infectivity, the median lethal dose (LD50) for many members remains limited or non-existent, thus restraining medical countermeasure (MCM) investigations. Mayaro virus (MAYV), o’nyong-nyong virus (ONNV), Una virus (UNAV), and Ross River virus (RRV) are four arthritogenic alphaviruses with epidemic potential. However, at the time of our study, no literature examining LD50 values for each virus in IFNAR-deficient mice, an effective model for characterizing disease severity and thus MCM potential, was available. In this study, we subcutaneously inoculated IFNAR-deficient mice with ranged doses of MAYV, ONNV, UNAV, or RRV to determine the LD50. However, we were unsuccessful upon finding complete lethality across all ranged doses for each virus. We further validated MCM potential in our MAYV model by prophylactically treating mice with neutralizing antibody (nAb) and examining clinical scores, weight loss, and survival rates. Our study serves as the first to examine the lethality of UNAV, MAYV, and RRV infection in an IFNAR-deficient mouse model and provides crucial lethal dose reference material for future MAYV, ONNV, UNAV, and RRV studies.