BACKGROUND: Since medication nonadherence is considered to be an important health risk, numerous interventions to improve adherence have been developed. During the past decade, the use of Internet-based interventions to improve medication adherence has increased rapidly. Internet interventions have the potential advantage of tailoring the interventions to the needs and situation of the patient. OBJECTIVE: The main aim of this systematic review was to investigate which tailored Internet interventions are effective in improving medication adherence. METHODS: We undertook comprehensive literature searches in PubMed, PsycINFO, EMBASE, CINAHL, and Communication Abstracts, following the guidelines of the Cochrane Collaboration. The methodological quality of the randomized controlled trials and clinical controlled trials and methods for measuring adherence were independently reviewed by two researchers. RESULTS: A total of 13 studies met the inclusion criteria. All included Internet interventions clearly used moderately or highly sophisticated computer-tailored methods. Data synthesis revealed that there is evidence for the effectiveness of Internet interventions in improving medication adherence: 5 studies (3 high-quality studies and 2 low-quality studies) showed a significant effect on adherence; 6 other studies (4 high-quality studies and 2 low-quality studies) reported a moderate effect on adherence; and 2 studies (1 high-quality study and 1 low-quality study) showed no effect on patients' adherence. However, most studies used self-reported measurements to assess adherence, which is generally perceived as a low-quality measurement. In addition, we did not find a clear relationship between the quality of the studies or the level of sophistication of message tailoring and the effectiveness of the intervention. This might be explained by the great difference in study designs and the way of measuring adherence, which makes results difficult to compare. There was also large variation in the measured interval between baseline and follow-up measurements. CONCLUSION: This review shows promising results on the effectiveness of Internet interventions to enhance patients' adherence to prescribed long-term medications. Although there is evidence according to the data synthesis, the results must be interpreted with caution due to low-quality adherence measurements. Future studies using high-quality measurements to assess medication adherence are recommended to establish more robust evidence for the effectiveness of eHealth interventions on medication adherence.