Episodic ataxia type 2 (EA2) is an inherited autosomal dominant disorder related to cerebellar dysfunction and is associated with mutations in the pore-forming _1A subunits of human P/Q-type calcium channels (Ca_V2.1 channels). The majority of EA2 mutations result in significant loss-of-function phenotypes. Whether EA2 mutants may display dominant-negative effects in human, however, remains controversial. To address this issue, five EA2 mutants in the long isoform of human _1A subunits were expressed in Xenopus oocytes to explore their potential dominant-negative effects. Upon coexpressing the cRNAs of _1A WT with each _1A mutant in molar ratios ranging from 1:1 to 1:10, the amplitude of barium currents through wild-type Ca_V2.1 channels decreased significantly as the relative molar ratio of _1A mutants increased, suggesting the presence of an _1A mutant-specific suppression effect. When we coexpressed 1A WT with proteins not known to interact with Ca_V2.1 channels, no significant suppression effects were observed. Furthermore, increasing the amount of auxiliary subunits resulted in partial reversal of the suppression effects in nonsense, but not missense EA2 mutants. On the other hand, when we repeated the same coinjection experiments of _1A WT and mutant by using a splice variant of _1A subunit that contained a considerably shorter carboxyl-terminus (the short isoform), no significant dominant-negative effects were noted until we enhanced the relative molar ratio to 1:10. Taken together, these results indicate that for human wild-type Ca_V2.1 channels comprising the long _1A subunit isoform, both missense and nonsense EA2 mutants indeed display prominent dominant-negative effects.