© 2017, Springer International Publishing Switzerland. Purpose: To report the results of a randomized controlled trial using an electronic monitoring device (EM) plus a motivational interviewing (MI) intervention to enhance adherence to disease-modifying therapies (DMT) in pediatric MS. Methods: Fifty-two youth with MS (16.03 ± 2.2 years) were randomized to receive either MI (n = 25) (target intervention) or a MS medication video (n = 27) (attention control). Primary endpoint was change in adherence. Secondary outcomes included changes in quality of life, well-being and self-efficacy. Random effects modeling and Cohen’s effect size computation evaluated intervention impact. Results: Longitudinal random effect models revealed that the MI group decreased their EM adherence (GroupxTime interaction = −0.19), while increasing frequency of parental DMT reminder (26.01)/administration (11.69). We found decreased EM use in the MI group at 6 months (Cohen’s d = −0.61), but increased pharmacy refill adherence (d = 0.23). Parental reminders about medication increased in MI subjects vs controls (d = 0.59 at 3 months; d = 0.70 at 6 months). We found increases in self-reported adherence (d = 0.21) at 3 but not 6 months, fewer barriers to adherence at three (d = −0.58) and six months (d = −0.31), better physical (d = 0.23 at 3 months; d = 0.45 at 6 months), emotional (d = 0.25 at 3 months) and self-efficacy function (d = 0.55 at 3 months; 0.48 at 6 months), but worse well-being, including self-acceptance (d = −0.53 at 6 months) and environmental mastery (d = −0.42 at 3 and 6 months) in intervention as compared to control patients. Conclusions: Participants receiving MI + EM experienced worsening on objective measures of adherence and increased parental involvement, but improved on some self- and parent-reported measures. MI participants reported improvements in quality of life and self-efficacy, but worsened well-being.