Aims: The goals of the study were to evaluate participant engagement and effects of an Internet-based, self-directed program for depressive symptoms. We compared outcomes of adults with multiple sclerosis (MS) with those of adults with other chronic diseases. Methods: This was a secondary analysis of a randomized controlled pilot study. Data were explored for differences between people diagnosed with MS and those with other chronic disease diagnoses. Data were obtained from 47 participants who participated in the original parent study (11 had MS). Participants with at least a moderate preexisting depressive symptom burden on the Patient Health Questionnaire (PHQ) were randomly divided into either a control group or the 8-week “Think Clearly About Depression” online depression self-management program. Study tools were administered at baseline, week 4, and week 8 to evaluate whether the online program improved depressive symptom self-management. Analysis examined differences between participants with and without an MS diagnosis in the treatment and control groups. Results: Average baseline depressive symptom burdens were severe for those with MS and those without MS as measured by the PHQ. Number needed to treat analysis indicated that 1 in every 2 treatment group participants with MS found clinically significant reductions in depressive symptoms by week 8. All participants with MS completed all online program modules. When compared with those with other chronic diseases, participants with MS showed a trend toward greater improvements in the PHQ and health distress scores in addition to self-efficacy in exercising regularly, social/recreational activities, and controlling/managing depression at the end of 8 weeks. Conclusions: An online depressive symptom self-management program is acceptable to people with MS and may be helpful to address undertreated depressive symptoms. The number of participants limits available statistics and ability to generalize results.