Objective: This study aimed to estimate the prevalence of substance use in the Norwegian general population and examine whether the risk of various psychiatric or somatic diseases varied according to alcohol-and substance use. Methods: A survey was distributed to 5500 persons in Norway, and a sample of 1792 persons responded (36% response rate). Data concerned with the use of substances were cross-tabulated with disease occurrence, and relative ratios (RR) of diseases in groups of lifetime substance users versus abstainers/ low frequent users were calculated. Results: Lifetime prevalence estimates were 83.5% for alcohol, 7.9% for cannabis, 8.5% for sedatives, 33.8% for strong analgesics and 2.4% for opioids and for stimulants. Drinking alcohol weekly or daily was associated with lower risk of several diseases, whereas lifetime use of sedatives, strong analgesics and opioids was associated with higher risk. Lifetime use of cannabis was associated with higher risk of depression and lower risk of diabetes and arthrosis. Conclusions: While frequent alcohol use was associated with reduced risk of several diseases, lifetime use of other substances was generally associated with higher risk of disease. The study provides evidence of increased risk of disease among users of illicit substances and prescription drugs.