Drug-drug interactions (DDIs) are an important type of adverse drug events. Yet overall incidence and pattern of DDIs in Iran has not been well documented and little information is available about the strategies that have been used for their prevention. The purpose of this study was to systematically review the literature on the incidence and pattern of DDIs in Iran as well as the used strategies for their prevention. PubMed, Scopus, electronic Persian databases, and Google Scholar were searched to identify published studies on DDIs in Iran. Additionally, the reference lists of all retrieved articles were reviewed to identify additional relevant articles. Eligible studies were those that analyzed original data on the incidence of DDIs in inpatient or outpatient settings in Iran. Articles about one specific DDI and drug interactions with herbs, diseases, and nutrients were excluded. The quality of included studies was assessed using quality assessment criteria. Database searches yielded 1053 potentially eligible citations. After removing duplicates, screening titles and abstracts, and reading full texts, 34 articles were found to be relevant. The quality assessment of the included studies showed a relatively poor quality. In terms of study setting, 18 and 16 studies have been conducted in inpatient and outpatient settings, respectively. All studies focused on potential DDIs while no study assessed actual DDIs. The median incidence of potential DDIs in outpatient settings was 8.5% per prescription while it was 19.2% in inpatient settings. The most indicated factor influencing DDIs incidence was patient age. The most involved drug classes in DDIs were beta blockers, angiotensin-converting-enzyme inhibitors (ACEIs), diuretic agents, and non-steroidal anti-inflammatory drugs (NSAIDs). Thirty-one studies were observational and three were experimental in which the strategies to reduce DDIs were applied. Although almost all studies concluded that the incidence of potential DDIs in Iran in both inpatient and outpatient settings was relatively high, there is still no evidence of the incidence of actual DDIs. More extensive research is needed to identify and minimize factors associated with incidence of DDIs, and to evaluate the effects of preventive interventions especially those that utilize information technology.