Preclinical evidence shows that β-adrenoceptor antagonists (β-blockers) inhibit tumor and metastasis progression in animal models of melanoma. We hypothesized that the use of β-blockers for concomitant diseases is associated with a reduced risk of progression of thick (Breslow thickness >1 mm) malignant melanoma. Two patient subgroups were identified from the medical records of 121 consecutive patients with a thick melanoma. Of these, 30 patients had been prescribed β-blockers for 1 year or more (treated subgroup), whereas the other 91 were untreated. After a median follow-up time of 2.5 years, tumor progression was observed in 3.3% of the treated subgroup and in 34.1% of the untreated subgroup. The Cox model on progression indicated a 36% (95% confidence interval, 11%-54%) (P = .002) risk reduction for each year of β-blocker use. No deaths were observed in the treated group, whereas in the untreated group 24 patients died. To our knowledge, the present study suggests for the first time that exposure to β-blockers for 1 year or more is associated with a reduced risk of progression of thick malignant melanoma, indicating the need for larger epidemiological studies and randomized clinical trials.