Background: Current evidence for the effectiveness of specialist multidisciplinary programs for burdensome chronic pain and functional somatic syndromes drive effort to improve approaches, strategies, and delivery modes. It is unknown to what extent and in what respect serious gaming during regular outpatient rehabilitation can contribute to health outcomes. Objective: Study objectives are: to determine the effect of additional serious gaming on 1) physical and/or emotional functioning in general, 2) particular outcome domains, and 3) patient global impressions of change, general health, and functioning; and to determine 4) dependency of serious gaming effects on adherence. Methods: A naturalistic quasi-experiment with embedded qualitative methods was conducted. Intervention group patients received an additional guided (mindfulness based) serious gaming intervention ('LAKA') during week 9-12 of a 16-week rehabilitation program at 2 sites of a Dutch rehabilitation clinic. Simultaneously, 119 control group patients followed the same program without serious gaming at 2 similar sites of the same clinic. Data consisted of 10 semi-structured patient interviews and routinely collected patient self-reported outcomes. First, multivariate