The transition to daylight saving time (DST) is beneficial for energy conservation but at the same time it has been reported to increase the risk of cerebrovascular and cardiovascular problems. Here, we evaluate the effect of the DST shift on a whole spectrum of diseases—an analysis we hope will be helpful in weighing the risks and benefits of DST shifts. Our study relied on a population-based, cross-sectional analysis of the IBM Watson Health MarketScan insurance claim dataset, which incorporates over 150 million unique patients in the US, and the Swedish national inpatient register, which incorporates more than nine million unique Swedes. For hundreds of sex- and age-specific diseases, we assessed effects of the DST shifts forward and backward by one hour in spring and autumn by comparing the observed and expected diagnosis rates after DST shift exposure. We found four prominent, elevated risk clusters, including cardiovascular diseases (such as heart attacks), injuries, mental and behavioral disorders, and immune-related diseases such as noninfective enteritis and colitis to be significantly associated with DST shifts in the United States and Sweden. While the majority of disease risk elevations are modest (a few percent), a considerable number of diseases exhibit an approximately ten percent relative risk increase. We estimate that each spring DST shift is associated with negative health effects–with 150,000 incidences in the US, and 880,000 globally. We also identify for the first time a collection of diseases with relative risks that appear to decrease immediately after the spring DST shift, enriched with infections and immune system-related maladies. These diseases’ decreasing relative risks might be driven by the documented boosting effect of a short-term stress (such as that experienced around the spring DST shift) on the immune system.