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Alcohol intake is known to influence serum high-density lipoprotein cholesterol (HDL-C), yet how drinking patterns shape this association is less researched. We examined whether frequency of drinking versus amount per occasion was differently related to HDL-C in a large population sample. Data were taken from a cross-sectional study of 18,614 respondents aged 40-79 years in the Tromsø general population health study. Alcohol use was assessed by self-report. Fasting HDL-C was measured using standardized laboratory protocols. Mean alcohol intake was 6.7 g/day and mean HDL-C 1.57 mmol/L. Total alcohol consumption correlated positively with HDL-C (r = 0.075; p < 0.001). In regression models, each additional gram/day was associated with an increase of 0.005 mmol/L HDL-C (95% CI 0.004-0.005; p < 0.001). Drinking frequency showed a positive correlation to HDL-C (r = 0.183; p < 0.001), whereas amount per occasion was inversely related to HDL-C (r = -0.128; p < 0.001). A significant frequency × amount interaction indicated that higher amounts per occasion were linked to lower HDL-C primarily among the infrequent drinkers (p < 0.001). The results indicate that the alcohol-HDL-C association was driven by how often alcohol was consumed rather than how much was consumed per occasion. Frequent, lower-dose drinking related to higher HDL-C, whereas infrequent, higher-dose occasions related to lower HDL-C. These findings underscore the need to consider drinking patterns, beyond average intake, when interpreting HDL-C and appraising alcohol-related cardiovascular risk.