BackgroundCurrent evidence for the effectiveness of specialist multidisciplinary programs for burdensome chronic pain and functional somatic syndromes drives the effort to improve approaches, strategies, and delivery modes. It remains unknown to what extent and in what respect serious gaming during the regular outpatient rehabilitation can contribute to health outcomes.ObjectiveThe objectives of our study were to determine the effect of additional serious gaming on (1) physical and emotional functioning in general; (2) particular outcome domains; and (3) patient global impressions of change, general health, and functioning and to determine (4) the dependency of serious gaming effects on adherence.MethodsWe conducted a naturalistic quasi-experiment using embedded qualitative methods. The intervention group patients received an additional guided (mindfulness-based) serious gaming intervention during weeks 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 semistructured patient interviews and routinely collected patient self-reported outcomes. First, multivariate linear mixed modeling was used to simultaneously estimate a group effect on the outcome change between weeks 8 and 16 in 4 primary outcomes: current pain intensity, fatigue, pain catastrophizing, and psychological distress. Second, similar univariate linear mixed models were used to estimate effects on particular (unstandardized) outcomes. Third, secondary outcomes (ie, global impression of change, general health, functioning, and treatment satisfaction) were compared between the groups using independent t tests. Finally, subgroups were established according to the levels of adherence using log data. Influences of observed confounding factors were considered throughout analyses.ResultsOf 329 eligible patients, 156 intervention group and 119 control group patients (N=275) with mostly chronic back pain and concomitant psychosocial problems participated in this study. Of all, 119 patients played ≥75% of the game. First, the standardized means across the 4 primary outcomes showed a significantly more favorable degree of change during the second part of the treatment for the intervention group than for the control group (beta=−0.119, SE=0.046, P=.009). Second, the intervention group showed a greater outcome change in depressive mood (b=−2.748, SE=1.072, P=.011) but not in “insufficiency” or concentration problems. Third, no significant group effects on secondary outcomes were found. Fourth, adherence was generally high and invariant.ConclusionsThe findings of this study suggest a very small favorable average effect on relevant health outcomes of additional serious gaming during multidisciplinary rehabilitation. The indication that serious gaming could be a relatively time-efficient component warrants further research into if, when, how, and for which patients serious gaming could be cost-effective in treatment and why.Trial RegistrationNetherlands Trial Registry NTR6020; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6020 (Archived by WebCite at http://www.webcitation.org/71IIoTXkj)