Abstract Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and is highly fatal. We report the results of a strategy that included identification of individuals with severe ICI-myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with CTLA4-fusion protein abatacept and the Janus-kinase inhibitor ruxolitinib. Forty cases with definite ICI-myocarditis were included with pathological confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. Abatacept dose was adjusted using CD86-receptor occupancy on circulating monocytes. Myotoxicity-related fatality rate was 3.4%(1/30) in these 30 patients vs.60% in 1st quartile(p<0.0001). These clinical results are hypothesis-generating and need further evaluation.