Analgesic drugs like acetylsalicylic acid, paracetamol, and ibuprofen are frequently used by subjects suffering from headache of acute mountain sickness (AMS). It is not clear if the effect is due to analgesia or prevention of AMS. We performed a randomized controlled clinical trial comparing a low dose of an acetylsalicylic acid analog, calcium carbasalate (380 mg /day), to placebo in a cohort of altitude-naïve subjects attempting a fast climb of Mt. Kilimanjaro (5896 m). A third noncontrolled open arm was proposed-the usual recommended preventive treatment of acetazolamide 500 mg/day. Of 93 potential participants, 44 chose prevention with acetazolamide, 18 refused participation, 15 received calcium carbasalate, and 16 received placebo. Mean age was 39 +/- 9 (SD) yr and 15% were female. AMS was quantified by the Lake Louise Symptom Score and physician assessment. Calcium carbasalate at 380 mg/day did not have any preventive effect on AMS and did not have any effect on the prevalence and intensity of headache. Event rate of AMS in the pooled carbasalate-placebo group was 84% and 55% in the acetazolamide group. The number needed to treat (NNT) at 500 mg/day of acetazolamide was 3. One subject on acetazolamide developed high altitude cerebral edema and was treated with dexamethasone, oxygen, and descent by evacuation. In conclusion, low-dose calcium carbasalate is not effective for prevention of AMS. In addition, these results corroborate the contention that in typical steep climbing profile settings, such as used by commercial enterprise on Mt. Kilimanjaro, acetazolamide 500 mg/day may not be sufficient to prevent AMS or to sufficiently reduce symptom intensity in almost half of subjects.