This study presents a record of Holocene surface runoff events and several large earthquakes, preserved in the sediments of pre-Alpine Lake Iseo, northern Italy. A combination of high-resolution seismic surveying, detailed sediment microfacies analysis, non-destructive core-scanning techniques and AMS 14C dating of terrestrial macrofossils was used to detect and date these events. Based on this approach, our data shed light on past seismic activity in the vicinity of Lake Iseo and the influence of climate variability and human impact on allochthonous detrital matter flux into the lake. The 19 m long investigated sediment sequence of faintly layered lake marl contains frequent centimetre- to decimetre-scale sandy-silty detrital layers. During the early to mid Holocene, these small-scale detrital layers, reflecting sediment supply by extreme surface runoff events, reveal a distinct centennial-scale recurrence pattern. This is in accordance with regional lake-level highstands and minima in solar activity and thus apparently mainly climate-controlled. After c. 4200 cal. yr BP, intervals of high detrital flux occasionally also correlate with periods of enhanced human settlement activity. In consequence, deposition of small-scale detrital layers during the late Holocene apparently reflects a rather complex interplay between climatic and anthropogenic influences on catchment erosion processes. Besides the small-scale detrital layers, five up to 2.40 m thick large-scale detrital event layers, composed of basal mass-wasting deposits overlain by large-scale turbidites, were identified, which are supposed to be triggered by strong earthquakes. The uppermost large-scale event layer can be correlated to a documented Mw=6.0 earthquake in ad 1222 in Brescia. The four other large-scale event layers are supposed to correspond to previously undocumented local earthquakes. These occurred around 350 bc, 570 bc, 2540 bc and 6210 bc and most probably also reached magnitudes in the order of Mw = 5.0-6.5.