Background: Equine exertional rhabdomyolysis (ER) syndrome is a myopathy characterised by repeated episodes of muscle fibre damage induced by exercise. Whilst ER syndrome is heritable, previous studies have not identified causal variants nor pathophysiological mechanisms. The disorder has welfare and financial implications, but despite this, a performance advantage has been identified in susceptible racing Standardbreds. Objectives: To assess whether artificial selection and inbreeding are associated with increasing susceptibility to ER syndrome in horses. Study design: Case-control study. Methods: We used genetic data from 33 Connemaras (CP) and 94 Warmbloods (WB) to calculate Wright’s fixation index (F _ST), runs of homozygosity (ROH), genomic inbreeding, and to model inbreeding depression both within and across the two breeds. Results: Signatures of selection were identified both in WB and across breeds; CP had elevated F _ST values across the genome, indicating a higher degree of differentiation. When using a hierarchical F _ST model, a greater degree of differentiation was captured when disease state was nested within breed. ROHs in ER WBs were associated with an overrepresentation of cyclic AMP signalling pathway genes, and a greater proportion of large (>16Mb) ROHs were identified in ER-susceptible WBs, indicative of recent inbreeding. ER WBs had significantly higher (U=1414.0, p=0.018) inbreeding coefficients (F _ROH) than controls, however inbreeding depression models did not have good predictive ability. Main limitations: Small sample size, particularly for inbreeding depression modelling and within CP, and results present associations rather than proven causality. Conclusions: In summary, ER appears to have different genetic background in different breeds, with potential contributing effects of artificial selection in CP and of inbreeding in WB. Although a difference in inbreeding between WB cases and controls was observed, a specific effect of inbreeding depression was not supported.