The present study investigated the hypothesis that the magnitude of negative interpretation bias displayed by those with depression is related to the degree of depression they experience. Seventy one depressed participants (scoring 14 and above on the Beck Depression Inventory II) completed tasks spanning three domains of possible negative interpretations: semantic ambiguity; nonverbal ambiguity and situational ambiguity. Regression analyses revealed that just under half of the variance in depressive symptom severity was explained by the combination of negative interpretation bias tasks, with the strongest predictor of depressive symptom severity being negative interpretation of semantic ambiguity when reading ambiguous text descriptions. Subsidiary group analyses confirmed that severely depressed individuals interpreted emotionally ambiguous information in a more negative way than did their mildly or moderately depressed counterparts. These findings indicate that the degree of negative interpretive bias is closely related to depression severity and that bias manifests especially strongly at the most severe levels of depression. Our findings may help us to refine cognitive theories of depression and be helpful in guiding therapy.