The relationship between treatment with histamine-2 (H2)-receptor antagonists (cimetidine and ranitidine) and subsequent risk of gastric cancer was analyzed with data of a case-control study conducted in northern Italy between 1983 and 1991 on 628 incident cases of gastric cancer and 1776 control subjects who had been hospitalized for acute, nonneoplastic, non-digestive-tract disorders, with a specific focus on time-risk relationships and analysis of covariates. Previous use of H2-receptor antagonists was reported by 45 (7.2%) cancer patients and 68 (3.8%) control subjects; the corresponding multivariate relative risk (RR) was 2.1 (95% confidence interval [CI] 1.4-3.8). A significantly elevated risk, however, was evident only among individuals (27 patients and 23 control subjects) who had started using the drug less than 5 yr before diagnosis (RR 3.8, 95% CI 2.1-6.1). The risk estimate declined to 2.1 (95% CI 1.0-4.2) for use starting 5-9 yr before diagnosis and to 0.4 (95% CI 0.2-1.2) for use starting greater than or equal to 10 yr before diagnosis. When the relationship between use of H2-receptor antagonists and gastric cancer risk was examined across strata of sex, age, and other selected covariates (educational level, tobacco use, and alcohol and coffee consumption), all RRs were greater than unity for use starting less than 5 yr before diagnosis, but there was no evidence of any consistent association for use starting in the more distant past. Furthermore, there was no evidence of heterogeneity in the RRs for H2-receptor antagonist use and gastric cancer across strata of the covariates examined.(ABSTRACT TRUNCATED AT 250 WORDS)