Background Thyroid ultrasound to assess for nodular growth is commonly performed during the follow-up of patients with benign thyroid nodules, with the goal of identifying patients with a missed diagnosis of thyroid cancer. The objective of this study was to summarize the evidence regarding the diagnostic accuracy of growth during follow-up of benign thyroid nodules for thyroid cancer. Methods We searched multiple electronic databases using a search strategy designed by an experienced medical librarian from inception to March 2015. Eligible studies included patients with benign thyroid nodules assessed for growth during follow-up and evaluated for thyroid cancer either by surgical histology or a repeat fine needle aspiration biopsy. Reviewers working independently and in duplicate recorded data and assessed each study. Results The seven eligible studies lacked safeguards against bias and generated results that were imprecise with wide confidence intervals and inconsistent across studies. This warrants very low confidence in these results. The odds of nodule growth in patients with thyroid cancer on histopathology over these odds in patients without thyroid cancer (diagnostic odds ratio) was 0·58 (95% CI: 0·26-1·3); the diagnostic odds ratio was 2·2 (95% CI: 0·26-18) when an abnormal repeat biopsy was the reference standard. Conclusion The body of evidence linking nodule growth with thyroid cancer during the follow-up of benign nodules warrants very low confidence. In the era of high-value health care, the commonplace practice of following benign thyroid nodules with serial ultrasound assessment of growth to diagnose cancer can be questioned, calling for imminent evaluation.