This study aimed to determine the efficacy, tolerability, and practicality of acetazolamide for the prevention of acute mountain sickness (AMS) in Nepali trekking porters early in the trekking season. This study was a randomized, double-blind controlled trial with 400 male Nepali porters in the Mount Everest region of Nepal, trekking from Namche Bazaar (3440 m) to Lobuche (4930 m), the study endpoint. Participants were randomized to receive 250 mg acetazolamide daily or placebo, and AMS symptom scores (Lake Louise) were compared in highlanders vs lowlanders. Only 109 (27.2%) of the 400 porters completed the trial (28 highlanders, 81 lowlanders). The rest either dropped out (275/400 porters, 68.8%) or were excluded (16/400 porters, 4%). Acute mountain sickness occurred in 13 (11.9%) of 109 porters; all were lowlanders; 7 were taking acetazolamide, 6 taking placebo. Birthplace, acclimatization in the week before the trial, ascent rate, and rest days were the most important variables affecting the incidence of AMS. No highlanders, but 13 (16.1%) of 81 lowlanders had AMS (P = .016). Acclimatization in the pretrial week reduced AMS incidence (P = .013), as did a slower ascent rate (P = .0126), but rest days were the most potent prophylactic variable (P = .0001). Side effects were more frequent in porters taking acetazolamide than in the placebo group (P = .0001), but there were no serious side effects. Acetazolamide was tolerable, but impractical for the routine prevention of AMS in Nepali porters. A good trekking schedule and adequate acclimatization remain the most effective preventive measures. This study identified lowland porters as a high-risk group for developing AMS.