Influences of lifestyle habits and p53 codon 72 and p21 codon 31 polymorphisms on the risk for developing primary gastric cancer were examined in 89 gastric adenocarcinoma cases (51 males, 38 females) and 192 controls (106 males, 86 females) in a hospital-based, case-control study in Taiwan. In the final regression model, Helicobacter pylori infection and substance use (cigarette smoking, areca chewing) were significant predictors of risk for developing gastric cancer. Compared with subjects negative for H. pylori infection, positive subjects were 3.65-fold (95% CI = 2.07-6.42) more likely to develop gastric cancer. Compared with non-smokers or non-chewers, subjects with more than a 15 pack-year history or more than a 498 betel-year history (about 20 betel quids/day for 25 years) were 2.27- and 4.86-fold more at risk (95% CI = 1.06-4.84 and 1.20-19.74), respectively. Frequencies of arg/arg, arg/pro and pro/pro in p53 were 11 (12.4%), 53 (59.5%) and 25 (28.1%) in carcinoma cases and 40 (20.8%), 95 (49.5%) and 57 (29.7%) in control cases, respectively. Frequencies of arg/arg, ser/arg and ser/ser in p21 were 26 (29.2%), 36 (40.5%) and 27 (30.3%) in carcinoma cases and 49 (25.5%), 94 (49.0%) and 49 (25.5%) in control cases, respectively. Neither p53, nor p21 polymorphisms were significantly different in cases and controls ( P = 0.16 and P = 0.41, respectively). Results remained insignificant after dichotomizing with respect to cigarette smoking, areca chewing and H. pylori infection. In summary, our data indicate that in Taiwan, H. pylori infection, smoking and areca chewing are significant risk predictors for developing gastric cancer. p53 codon 72 and p21 codon 31 genotypes did not modify these risks.