OBJECTIVES: Poor compliance is the primary reason for suboptimal clinical benefit, especially in patients with chronic diseases. Fixed-dose combinations (FDC) and unit-of-use packaging (UUP) are strategies designed to simplify medication regimen and potentially improve compliance. The aim of our study is to systematically analyze the effect of FDC and UUP on compliance and effectiveness in patients with hypertension (HTA), dyslipidemia, AIDS, asthma and diabetes type 2 (DMII). METHODS: Systematic review (SR) of studies that compare medications combined in a single pill or within a UUP with the same free-drug combinations in HTA, AIDS, asthma and DMII. Bibliographic databases were searched from inception to February 2008 with no date limits. Two reviewers scrutinized retrieved references and full publications sought of potentially relevant studies were identified on the basis of title and/or abstract. Additional relevant studies were identified from manual searches. Only studies published in English or Spanish were included. Quality of studies was assessed using specific instruments according to their design. RESULTS: A total of 11 original studies (HTA 5; DMII 3; AIDS 2; dyslipidemia 1), 1 SR and 1 metaanalysis of varying quality were included in the SR. Most originals were retrospective (72%), based on medical claims (72%) and used medication possession ratio (RPM) as a proxy of compliance (54%).  Some studies also included self-reported compliance (27%) and measures of persistence (18%). Only 3 studies reported comparative effectiveness. Follow-up periods ranged from 16 weeks to 1 year. Overall, results show a tendency for better compliance and less missed doses in the FDC and UPP groups compared to free-drug combination groups. Limited data support noninferiority of FDC and UUP in terms of effectiveness. CONCLUSIONS: FDC and UUP seem to improve compliance with no major effects on effectiveness in patients with chronic diseases. However, evidence is weak and large randomized controlled trials should be carried out.