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Practical limitations in epidemiologic research may necessitate use of only a few questions for assessing the complex phenomenon called “stress.” The objective of this study was to evaluate the measurement characteristics of 2 single-item measures on the amount of stress and the ability to handle stress.We selected 218 adults age 50 to 76 years living in western Washington state from a large prospective cohort study of lifestyle factors and cancer risk to evaluate the 3-month test–retest reliability and intermethod reliability of the stress questions. To assess the latter, we compared 2 single-item measures on stress with 3 more fully validated multi-item instruments on perceived stress, daily hassles, and life events, which assessed the same underlying constructs as the single-item measures.The test–retest reliabilities for the single-item stress measures were good (kappa and intraclass correlations between 0.66 and 0.74). The intermethod reliabilities comparing the 2 single-item stress measures with 3 multi-item instruments were moderate (r = 0.31–0.46) and comparable to correlations observed among the 3 multi-item instruments (r = 0.25–0.47).The 2 single-item stress measures are reliable at measuring stress with validity similar to longer questionnaires. Single-item measures offer a practical instrument for assessing stress in large prospective epidemiologic studies that lack space for longer instruments.