Summary Background Actinic keratoses (AKs) are premalignant skin lesions, which, if left untreated, can develop into squamous cell carcinoma. Current treatments for AKs are destructive and are often associated with significant adverse events. The development of an effective and well‐tolerated topical treatment for AK is desirable.

Objectives To evaluate the efficacy and safety of 3·0% diclofenac in 2·5% hyaluronan gel as a treatment for AK.

Methods This was a multicentre, double‐blind, placebo‐controlled study in which 195 patients with at least five AKs in up to three designated treatment blocks were randomized to four treatment groups. Patients randomized into the active treatment groups A30 (n = 49) and A60 (n = 48) received topical treatment with 3·0% diclofenac in 2·5% hyaluronan gel 0·5 g twice daily for 30 or 60 days, respectively. Patients in the placebo (vehicle gel) groups V30 (n = 49) and V60 (n = 49) received topical treatment with 2·5% hyaluronan gel 0·5 g twice daily for 30 or 60 days, respectively. Treatment efficacy was assessed by target and cumulative lesion number scores (TLNS and CLNS, respectively) and lesion total thickness score (TTS). Investigator and patient global improvement indices (IGII and PGII) were also used to rate overall improvement.

Results Compared with placebo, significantly more patients given active treatment for 60 days had TLNS = 0 (33% vs. 10%, P < 0·05; an improvement of 64% compared with 34% with placebo), CLNS = 0 (31% vs. 8%, P < 0·05; an improvement of 54% compared with 23% with placebo) and TTS = 0 (25% vs. 6%, P < 0·05; an improvement of 59% compared with 31% with placebo). The IGII and PGII scores were also significantly better when active treatment was compared with placebo (P < 0·05). Both treatments were generally well tolerated and the incidence of the most common adverse events was similar between groups.

Conclusions Treatment with 3·0% diclofenac in 2·5% hyaluronan gel was effective when used for 60 days and was well tolerated in patients with AK.