The aim of the study was to examine the effect of a 4-week classroom physical activity break intervention on middle school students' health-related physical fitness. The study was a randomized controlled trial with students assigned to the experiment and control conditions. A convenience sample comprised 94 adolescents (experiment group n = 52; control group n = 42) (48 females, 46 males, age range 11 to 15 years) from four classes in one school in the mid-south United States. Intervention was delivered with an Xbox One Kinetic system to minimize teachers-dependence when delivering the intervention. In addition, to acknowledge students' poor treatment adherence, which can occur in school-based intervention studies, analyses were conducted to both the intention-to-treat group and the students' who reached the 66.7% attendance rate benchmark. Analysis of covariance test results showed that for the intention-to-treat group there were no significant intervention effects on cardiovascular endurance (F[2,82] = 2.58, p = 0.112), upper body strength and endurance (F[2,84] = 3.55, p = 0.063), abdominal strength and endurance (F[2,82] = 0.01, p = 0.973), or flexibility (F[2,71] = 0.48, p < 0.489) tests. In addition, the analyses comparing the high attendance group to the control group showed that intervention had a moderate significant effect on students' cardiovascular endurance (F[2,52] = 23.95, p < 0.001, ?2 = 0.30) and a small effect on abdominal strength and endurance (F[2,52] = 3.24, p = 0.049, ?2 = 0.08). The results of this study highlighted the importance of school students' adherence to program to achieve intended and planned intervention benefits.