Venous blood collection systems (VBCSs) are combinations of in-vitro diagnostics and medical devices, usually available as integrated set. However, purchasing and using a combination of devices from different sets is considered by clinical laboratories as an option to achieve specific sampling tasks or reduce costs. This systematic review aimed to retrieve available evidence regarding safety, efficacy, and economic aspects of VBCSs, focusing on differences between integrated and combined systems. The literature review was carried out in PubMed. Cited documents and resources made available by scientific organisations were also screened. Extracted evidence was clustered according to Quality/Efficacy/Performance, Safety, and Costs/Procurement domains and discussed in the current European regulatory framework. Twenty documents published between 2010 and 2021 were included. There was no evidence to suggest equivalence between combined and integrated VBCSs in terms of safety and efficacy. Scientific society’s consensus documents and product standards report that combined VBCS can impact operators’ and patients’ safety. Analytical performances and overall efficacy of combined VBCSs are not guaranteed without whole system validation and verification. EU regulatory framework clearly allocates responsibilities for the validation and verification of an integrated VBCS, but not for combined VBCSs, lacking information about the management of product nonconformities and post-market surveillance. Laboratory validation of combined VBCS demands risk-benefit and cost-benefit analyses, a non-negligible organisational and economic burden, and investment in knowledge acquisition. Implications in terms of laboratory responsibility and legal liability should be part of a comprehensive assessment of safety, efficacy, and cost carried out during device procurement.