It is debated whether seasonal variation in outside temperature contributes to MS fatigue, one of the disease's most common symptoms. We analyzed the effect of the season on the baseline fatigue levels in our randomized, placebo-controlled, crossover, double-blind trial, Treatment of Fatigue with Methylphenidate, Modafinil, and Amantadine in MS (TRIUMPHANT-MS) conducted in two sites with very different climates. Fatigue was measured using two validated instruments (Modified Fatigue Impact Scale (MFIS) and Neuro-QoL fatigue score). MFIS scores varied with season and study site, while Neuro-QoL fatigue scores did not. The impact of temperature on multiple sclerosis fatigue depends on the specific patient-reported outcome measure employed.