SummaryBackground Pain is a common adverse effect of dermatological laser procedures. Currently, no standard topical anaesthetic cream exists for deeper dermal laser procedures. Objectives To compare the efficacy of lidocaine/tetracaine cream and lidocaine/ prilocaine cream in reducing self-reported pain during deeper dermal laser treatment of acne keloidalis nuchae (AKN) and tattoos. Methods We conducted two randomized, double-blind, controlled clinical trials with intrapatient, split-lesion designs: study A included patients with AKN (n = 15); study B included patients with black tattoos (n = 15). The primary end point was the patients' self-reported pain on a 10-cm visual analogue scale (VAS). Secondary objectives were the percentage of patients with adequate pain relief, willingness to pay €25 for the cream that provided the best pain relief and safety of the creams. Results In both studies, VAS scores were lower for lidocaine/prilocaine cream, with a mean VAS difference in study A of 1Á9 [95% confidence interval (CI) 1Á0-2Á8] and in study B of 0Á6 (95% CI À0Á7 to 1Á9). In study A, adequate pain relief was achieved in 13% (n = 2) with lidocaine/tetracaine cream vs. 73% (n = 11) with lidocaine/prilocaine cream (P = 0Á004), and in study B in 53% (n = 8) vs. 80% (n = 12), respectively (P = 0Á289). In study A, 47% (n = 7) were willing to pay an additional €25 vs. 73% (n = 11) in study B. No serious adverse events occurred. Conclusions Lidocaine/prilocaine cream under plastic occlusion is the preferred topical anaesthetic during painful laser procedures targeting dermal chromophores.