In a randomized, single-blind, 28-day study, a new high strength capsaicin cream (0.25%) applied twice daily (n = 31) was compared with four-times-daily application of low strength capsaicin cream (0.025%; n = 29) for the treatment of pain associated with osteoarthritis. High strength capsaicin provided greater pain relief with a more rapid onset of action when compared with lower strength capsaicin. After 2 days of treatment, pain severity was reduced by 48.0 +/- 7.7% in the 0.25% capsaicin treatment group (p < 0.001 vs. baseline and p = 0.009 vs. low strength capsaicin) compared with a 17.7 +/- 8.1% reduction in the 0.025% capsaicin treatment group (p = 0.038 vs. baseline). Fifty-five percent of the patients using 0.25% capsaicin b.i.d. experienced at least a 50% reduction in pain severity after 2 days of treatment.By contrast, it was day 14 before one-half of the patients applying 0.025% capsaicin cream q.i.d. experienced a 50% reduction in pain severity. The most commonly reported adverse experience was a transient burning sensation after application of the cream. The incidence of burning with 0.25% capsaicin cream was greater than 0.025% capsaicin cream only on day 2 (69% vs. 31%, p = 0.006). Thereafter, daily reports of burning sensations after drug application declined rapidly in both treatment groups. The results demonstrate that 0.25% capsaicin cream applied b.i.d. is highly effective and well tolerated therapy for osteoarthritis pain.