The characteristics of stimuli that elicit skin conductance responses (SCRs) have been conceptualized in varied ways, with strong emphasis on the significance or arousing quality of stimuli. Our goal was to determine whether “significance” can be shown to have an effect on SCRs independent of “arousal,” using words as stimuli. Ratings of words indicated that significance is partially independent of arousal. In Study 1, SCRs from 43 participants during presentation of 20 significant, nonarousing words with a negative valence that were either depression related or potentially self-referent and 20 nonsignificant words matched on valence and arousal showed a main effect of significance. In Study 2 (N=44), significant, nonarousing words were sampled more broadly to examine the effects of self-reference and valence. Significance, rather than just negativity or self-reference, elicited SCRs independently of arousal. SCRs to significant words may reflect cognitive and attentional processes that, in turn, might prove useful for the assessment of the cognitive aspects of anxiety.