Use of hydrochlorothiazide and risk of skin cancer in a large nested case-control study in Spain

Pharmacoepidemiol Drug Saf. 2021 Sep;30(9):1269-1278. doi: 10.1002/pds.5295. Epub 2021 Jun 8.


Purpose: Hydrochlorothiazide (HCTZ) use has been linked to skin cancer in northern European countries. We assessed the association between HCTZ exposure and risk of malignant melanoma (MM) and keratinocyte carcinoma (KC) in a European Mediterranean population.

Methods: Two parallel nested case-control studies were conducted in Spain using two electronic primary healthcare databases, each one providing data on both exposure and outcomes: SIDIAP and BIFAP. Cancer cases were matched to 10 controls by age and gender through risk-set sampling. The ORs and 95% CI for MM and KC associated with previous HCTZ use were estimated using conditional logistic regression. In BIFAP, KC cases were further identified as basal cell carcinoma (BCC) or squamous cell carcinoma (SCC).

Results: In adjusted analyses, both ever and cumulative high (≥50,000 mg) use of HCTZ were associated with an increased risk of KC. The risk estimates for high use were 1.30 (1.26-1.34) in SIDIAP and 1.20 (1.12-1.30) in BIFAP, with a lower risk for BCC (1.11 [1.02-1.21]) than for SCC (1.71 [1.45-2.02]). A dose-response relationship was observed between cumulative doses of HCTZ and KC risk. Inconsistent results were found for high use of HCTZ and risk of MM: 1.25 (1.09-1.43) in SIDIAP and 0.85 (0.64-1.13) in BIFAP.

Conclusions: In this European Mediterranean population, a high cumulative use of HCTZ was related to an increased risk of KC with a clear dose-response pattern.

Keywords: HCTZ; case-control; keratinocyte carcinoma; malignant melanoma; pharmacoepidemiology.

MeSH terms

  • Carcinoma, Basal Cell* / chemically induced
  • Carcinoma, Basal Cell* / epidemiology
  • Case-Control Studies
  • Humans
  • Hydrochlorothiazide / adverse effects
  • Skin Neoplasms* / chemically induced
  • Skin Neoplasms* / epidemiology
  • Spain / epidemiology


  • Hydrochlorothiazide