Introduction: The primary aim of this systematic review was to determine the safety, technical efficacy, and effectiveness of 48-hour wireless pH monitoring (WM) for gastroesophageal reflux disease (GERD), compared with no pH monitoring in patients who failed to tolerate a catheter. In the absence of eligible studies, the secondary aim was to determine these performance characteristics for WM relative to catheter-based pH monitoring (CBM) in patients suspected of GERD, who are able to tolerate a catheter. Methods: A protocol was registered on the PROSPERO database (CRD42013005852) before conducting the systematic review, which included the study selection criteria, and critical appraisal methods. Several key databases were searched to identify eligible comparative studies. Results: Chest pain occurred more often with WM compared with CBM; however, other adverse events were reported less frequently with WM. Technical failures, mostly due to attachment failures and early capsule detachments, were 3 times higher with WM, compared with CBM, [pooled relative risk (from meta-analysis)=3.3; 95% confidence interval, 1.63-6.81; I 2=0%; P=0.012; k=8). The sensitivity and specificity of WM varied widely, depending on type of analysis, monitoring time, capsule placement, reference standard, and diagnostic threshold. Discussion: WM is usually better tolerated than CBM but has more technical problems. Test accuracy was highly variable between studies; therefore, conclusions could not be drawn regarding the performance of the 2 tests. To make meaningful comparisons between WM and CBM a consensus is needed on the diagnostic threshold for GERD, monitoring time, appropriate capsule positioning, and the reference standard.