ObjectiveIn this systematic review on drug price comparison studies, we report on recent determinants of drug prices in a national and international context to facilitate regulation of drug prices by purchasers and policymakers worldwide. Determinants of drug prices were divided into non-modifiable and modifiable and were categorised as pertaining to a country’s income level, pharmaceutical market system and its policies and government.Primary outcomeDeterminants of drug prices or price variance.DesignWe systematically searched PubMed, EMBASE, Web of Science and Cochrane Library for peer-reviewed articles published between 2004 and 22 July 2020 that reported an association of the primary outcome with one or more determinants. We performed a best-evidence synthesis of these associations for determinants covered in at least three studies.Results31 publications were included. Only one publication described net drug prices and 30 described retail drug prices. Five modifiable determinants were associated with lower retail prices: generic market portion, discounts, tendering policies, central (governmental) purchasing and pricing regulation schemes. The originators market portion and a system in which mark-ups are common were associated with higher retail prices. Retail prices were highest in the USA, even compared with other high-income countries. A positive association between national income level and drug retail prices could not be established among middle-income and high-income countries. Retail prices were highest in low-income countries when adjusted for purchasing power parity.ConclusionsLiterature on determinants of net drug prices is extremely sparse. Various healthcare system interventions, market-specific and governmental regulations are consistently associated with lower retail prices. Some interventions are easily implementable in developing or middle-income countries, such as tendering, central purchasing and fixed pricing regulation schemes. Net drug price comparison studies are needed to overcome the lack of price transparency and to quantify the effectiveness of policy measures on net drug prices.