End-stage renal disease (ESRD) and its treatment are generally considered to be highly stressful and the associated loss of control over important life dimensions is believed to induce widespread depression. This situation was employed as a "living stress laboratory" in which to test the reformulated learned helplessness theory of depression. Results indicated that reduced perceived control over a variety of life dimensions was importantly related to increased depression, although the attributional reformulation of helplessness theory was not supported. Moreover, reanalyses of these data from a social learning theory perspective indicated that perceived self-efficacy contributed uniquely to this negative correlation in addition to expectancies regarding response-outcome contingency (Rotter I-E scores). The hypothesis that the negative correlation between depression and perceived control might also be explained in terms of patients' psychological differentiation and the intrusiveness of ESRD was subsequently examined. Results revealed that perceived intrusiveness contributed uniquely to perceived control and to affect, indicating that perceived control and intrusiveness each contribute independently to mood. Surprisingly, a low prevalence of clinical depression was observed, contradicting the general consensus that helplessness and depression are unavoidable psychological sequelae to ESRD. These findings are equally applicable to several other chronic and life-threatened patient populations (e.g., cancer, cardiac, diabetic) and thus underline the need for a general theory of the emotional impact of illness.