Abstract Ibuprofen has been shown to be more effective than placebo in the treatment of high altitude headache (HAH), but nonsteroidal anti-inflammatory agents have been linked to increased incidence of gastrointestinal (GI) side effects and high-altitude pulmonary edema (HAPE). We postulated that acetaminophen, which does not share ibuprofen’s theorized causal link to GI side effects or HAPE, could provide effective HAH therapy. We conducted a prospective, randomized, double-blind, clinical trial of ibuprofen vs. acetaminophen in the Solu Khumbu, Nepal: Mt. Everest Base Camp, Pheriche, Dingboche (4240 m to 5315 m). Seventy-four consecutive patients (ages 13 to 61 years) were randomized, were assessed with the Lake Louise Acute Mountain Sickness (AMS) criteria, and received a physical examination (which included vital signs, oxygen saturation as measured by pulse oximetry (SpO 2), and assessment of clinical Lake Louise AMS criteria). Patients then received either 400 mg of ibuprofen (IBU) or 1000 mg of acetaminophen (ACET), and were asked to rate their cephalgia using a 10-cm visual analog scale (VAS). Thirty-nine patients received IBU, and 35 received ACET. Baseline Lake Louise AMS scores were identical in the two groups (mean = 5.9). No differences in mean VAS scores between IBU and ACET groups were noted at time 0 (presentation), 30, 60, or 120 min. No cases of HAPE or high altitude cerebral edema were noted during the study period. In this study population, acetaminophen was as effective as ibuprofen in relieving the pain of HAH.