Importance: Diagnostic tests are often ordered by physicians in patients with a low pretest probability of disease to rule out conditions and reassure the patient.Objective: To study the effect of diagnostic tests on worry about illness, anxiety, symptom persistence, and subsequent use of health care resources in patients with a low pretest probability of serious illness.Evidence Acquisition: Systematic review and metaanalysis. We searched MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, PsychINFO, CINAHL, and ProQuest Dissertations electronic databases through December 31, 2011, for eligible randomized controlled trials. We independently identified studies for inclusion and extracted the data. Disagreements were resolved by discussion. We performed metaanalysis if heterogeneity was low or moderate (I 2 Ͻ50%).Results: Fourteen randomized controlled trials that included 3828 patients met the inclusion criteria and were analyzed with outcomes categorized as short term (Յ3 months) or long term (Ͼ3 months). Three trials showed no overall effect of diagnostic tests on illness worry (odds ratio, 0.87 [95% CI, 0.55-1.39]), and 2 showed no effect on nonspecific anxiety (standardized mean difference, 0.06 [Ϫ0.16 to 0.28]). Ten trials showed no overall long-term effect on symptom persistence (odds ratio, 0.99 [95% CI, 0.85-1.15]). Eleven trials measured subsequent primary care visits. We observed a high level of heterogeneity among trials (I 2 =80%). Meta-analysis after exclusion of outliers suggested a small reduction in visits after investigation (odds ratio, 0.77 [95% CI, 0.62-0.96]).Conclusions and Relevance: Diagnostic tests for symptoms with a low risk of serious illness do little to reassure patients, decrease their anxiety, or resolve their symptoms, although the tests may reduce further primary care visits. Further research is needed to maximize reassurance from medically necessary tests and to develop safe strategies for managing patients without testing when an abnormal result is unlikely.