Context Fatigue is common in life-limiting cancer. Methylphenidate (MPH), a psychostimulant, may be a useful therapy. Gathering evidence in patients with advanced cancer can be challenging. Objectives To determine if MPH improves cancer-related fatigue in people with advanced cancer. Methods N-of-1 trials are multicycle, double-blind, randomized, controlled crossover trials using standardized measures of effect in individuals. They are normally used to assess treatment effects in individuals. Aggregated N-of-1 trials from participants with end-stage cancer suffering fatigue were used to assess the group effect of MPH, producing an estimate of equivalent power to a parallel-group randomized controlled trial (RCT) but requiring less than half of the sample size. Up to three cycles of MPH 5 mg twice daily (three days) vs. identical placebo (three days) capsules were offered to participants. Primary outcome was improvement in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue Scale and the Wu Cancer Fatigue Scale. Analysis used Bayesian statistical methods using intention-to-treat principles. Results Forty-three participants completed 84 cycles of MPH and placebo in random order, exceeding sample size estimates. Overall, MPH did not improve fatigue (mean difference 3.2; 95% credible interval -2.0, 9.0; posterior probability of favorable effect 0.890). Eight participants showed important improvement, and one participant showed important worsening of fatigue on MPH. There were no features that distinguished participants whose fatigue responded to MPH compared with those who did not. Conclusion MPH does not improve fatigue in the population of patients with end-stage cancer. Aggregated N-of-1 trial methodology is feasible and produces population-based sample estimates with less than half the sample size required for the equivalent parallel-group RCT. It also identified individuals who did and did not respond to MPH, which is a feature difficult to achieve in a standard RCT. The study was registered with the Australian Clinical Trials Registry (12609000794202).