Myoclonus is often observed in epilepsy. It is characterized by sudden involuntary shock-like movements of the body (myoclonic jerks, MJs). This study examined whether epileptic myoclonus was under genetic control. Inbred strains of mice were administered eight daily flurothyl exposures, a 28-day rest period, and a final flurothyl retest. For all trials, the latency to the first MJ (threshold) and the number of MJs (MJ#) were recorded. The inbred strains that we examined exhibited significant variability in initial myoclonic response, and myoclonus across the eight flurothyl exposures. C57BL/6J and DBA/2J mice displayed significantly different initial latencies to a MJ, MJ# preceding a generalized seizure (GS), and changes in MJ threshold and MJ# across the eight seizure trials. [C57BL/6J x DBA/2J] F1-hybrid mice showed an initial MJ threshold and decreases in MJ threshold over the eight trials, which were similar to C57BL/6J; however, F1-hybrids had an initial MJ# and trend in MJ# over the eight trials that were similar to DBA/2J. Decreases in MJ threshold and MJ# following multiple seizure trials, observed in C57BL/6J mice, were dependent on the expression of GSs and not on MJ occurrence. Our study is the first to document the potential for genetic heterogeneity of myoclonus in mice; we show that significant alterations in myoclonic behavior occur after GSs. These results indicate that multiple GSs affect MJ thresholds. An understanding of the genetics of myoclonus will be important for determination of the brain areas responsible for myoclonus as well as for identification of candidate genes.