<jats:p>Background. Despite the rise of virtual reality (VR)-based interventions in stroke rehabilitation over the past decade, no consensus has been reached on its efficacy. This ostensibly puzzling outcome might not be that surprising given that VR is intrinsically neutral to its use—that is, an intervention is effective because of its ability to mobilize recovery mechanisms, not its technology. As VR systems specifically built for rehabilitation might capitalize better on the advantages of technology to implement neuroscientifically grounded protocols, they might be more effective than those designed for recreational gaming. Objective. We evaluate the efficacy of specific VR (SVR) and nonspecific VR (NSVR) systems for rehabilitating upper-limb function and activity after stroke. Methods. We conducted a systematic search for randomized controlled trials with adult stroke patients to analyze the effect of SVR or NSVR systems versus conventional therapy (CT). Results. We identified 30 studies including 1473 patients. SVR showed a significant impact on body function (standardized mean difference [SMD] = 0.23; 95% CI = 0.10 to 0.36; P = .0007) versus CT, whereas NSVR did not (SMD = 0.16; 95% CI = −0.14 to 0.47; P = .30). This result was replicated in activity measures. Conclusions. Our results suggest that SVR systems are more beneficial than CT for upper-limb recovery, whereas NSVR systems are not. Additionally, we identified 6 principles of neurorehabilitation that are shared across SVR systems and are possibly responsible for their positive effect. These findings may disambiguate the contradictory results found in the current literature.</jats:p>