One of the benefits of physical activity in people with profound intellectual and multiple disabilities (PIMD) is an increase in alertness. This study investigated the effect of a power-assisted exercise intervention on alertness and the relationship of this effect to the level of additional motor and visual impairments in people with PIMD. A randomized controlled trial design (N = 37) was used with five measurements. Using individual plots and multilevel analysis, differences in change of alertness over time were analyzed between the intervention and control group, as was the relationship of changes to additional impairments. Considerable variation in alertness over time was found. The results showed no difference between the control and intervention groups in terms of alertness. No relationship with additional impairments was found. This study underlines the importance of looking at the effectiveness of interventions for people with PIMD because those interventions may not be as effective as expected.