While altered motivation is central in sickness behavior, previous research has mainly focused on motivation for rewards, rather than motivational changes in a broader perspective. In a larger study following a randomized within-subject placebo-controlled crossover design, we investigated the effects of systemic inflammatory activation on self-rated motivation in 21 healthy participants, using an intravenous injection of 2.0 ng/kg body weight lipopolysaccharide (LPS) compared to an intravenous injection of saline (placebo). Self-rated motivation was measured before, 3 h, and 7.5 h post-injection using the Motivation Scale of Sickness (MOSSick), a newly developed tool designed to assess motivational changes during sickness. It contains 26 items covering motivational drives related to hunger, thirst, and food preferences; resting, physical, and social activities; care seeking; and utilization of resources (i.e., willingness to ‘pay’ and ‘walk’) to be able to rest or to be healthy at once. At the peak of the sickness response (3 h post-LPS injection), there was an increased motivation to seek care, rest, and sleep, as compared to placebo, while motivation to partake in physical and social activities decreased. Several of these effects remained at 7.5 h post-injection. When in the LPS condition, participants were also willing to pay more money to rest and to be healthy compared to when in the placebo condition. Hunger increased over time in both conditions, but less after LPS administration. During the peak of the sickness response, higher sickness ratings were weakly associated with lower motivation for social activities and higher motivation for resting and sleeping. No further association was found between motivational drives and sickness ratings or other sickness measures, i.e. concentrations of cytokines and tympanic temperature, although sample size was limited for these analyses. These findings illustrate that motivational changes during acute sickness are not restricted to a general decrease in motivation. Instead, sick individuals are more motivated to take part in behaviors that enable energy preservation, care, and recovery, compared to when healthy.