Prospective associations between quantity and frequency of alcohol consumption and cancer-specific mortality were studied using a nationally representative sample with pooled data from the 1988, 1990, 1991, and 1997-2004 administrations of the National Health Interview Survey (n = 323,354). By 2006, 8,362 participants had died of cancer. Cox proportional hazards regression was used to estimate relative risks. Among current alcohol drinkers, for all-site cancer mortality, higher-quantity drinking (≥ 3 drinks on drinking days vs. 1 drink on drinking days) was associated with increased risk among men (relative risk (RR) = 1.24, 95% confidence interval (CI): 1.09, 1.41; P for linear trend = 0.001); higher-frequency drinking (≥ 3 days/week vs. <1 day/week) was associated with increased risk among women (RR = 1.32, 95% CI: 1.13, 1.55; P-trend < 0.001). Lung cancer mortality results were similar, but among never smokers, results were null. For colorectal cancer mortality, higher-quantity drinking was associated with increased risk among women (RR = 1.93, 95% CI: 1.17, 3.18; P-trend = 0.03). Higher-frequency drinking was associated with increased risk of prostate cancer (RR = 1.55, 95% CI: 1.01, 2.38; P for quadratic effect = 0.03) and tended to be associated with increased risk of breast cancer (RR = 1.44, 95% CI: 0.96, 2.17; P-trend = 0.06). Epidemiologic studies of alcohol and cancer mortality should consider the independent effects of quantity and frequency.