Treatment response to methotrexate (MTX) for rheumatoid arthritis (RA) is not universal and non-adherence may partially explain this. The aims of this systematic review were to: (1) summarise existing rates of adherence to MTX, (2) identify predictors of adherence to MTX, and (3) assess the association between non-adherence and patient outcomes. The authors conducted a systematic search of papers published from January 1980 to February 2015 in PubMed, PsycINFO, EMBASE and CINAHL databases. Studies were eligible for inclusion if: (1) MTX was used as monotherapy or in combination with other therapies, (2) MTX was used in an RA or inflammatory polyarthritis population, (3) adherence was defined and measured as the extent to which patients followed their MTX regimen during the period of prescription, and (4) it was an original piece of research. In total, 10 studies met the inclusion criteria and 8 were evaluated as high quality. Rates of adherence ranged from 59% to 107%, and exposed differences in definitions of adherence, study methodologies and sample heterogeneity. A number of potential predictors of MTX adherence were identified; the strongest being related to beliefs in the necessity and efficacy of MTX, absence of low mood, mild disease and MTX monotherapy. Furthermore, 3 studies tested the association of adherence with disease activity as an outcome measure; all 3 found non-adherence associated with poor treatment response. This systematic review shows the importance of adherence to MTX treatment and summarises the associated modifiable factors.