High-resolution δ13C and δ18O records from upper Albian to lower Santonian pelagic carbonates of the Contessa Quarry section in Italy exhibit large positive oxygen isotopic excursions of ∼1‰ in the lower Cenomanian and upper Turonian–Coniacian strata. Within the uncertainties of biostratigraphic correlation, these positive excursions appear to correspond to times of large sea-level regressions in global sequence stratigraphic sea-level curves. Several lines of evidence suggest that the major δ18O excursions in Contessa reflect episodes of global cooling and not differential diagenesis. Numerical models of oxygen isotope exchange during diagenesis show that a high contrast in the degree of alteration would be required to produce these signals as artifacts of diagenesis, and lithological data provide no evidence for such large contrasts in the degree of alteration. Furthermore, although precise correlation with a section in the south of Spain is hampered by stratigraphic complexities, the general sequence of major positive δ18O excursions is reproduced. It is unlikely that differential diagenesis would produce similar artifacts in multiple sites. One explanation for the link between episodes of global cooling and sea-level falls is that global cooling events led to polar ice-sheet accumulation, lowering sea level. Although ice-free conditions have been inferred from evidence for a much warmer climate in Late Cretaceous time, our results suggest that the relationship between continental high-latitude ice sheets and overall climatic warmth warrants further examination.