More than a decade ago Singer (2009) described Gibraltar's experience with cholera and smallpox in 1865 as a syndemic. In this study, we provide a reassessment of that event and, consequently, propose a methodology to identify a syndemic at the population level. We propose that the concept of the harvesting effect from demographic studies on crisis mortality provides a useful framework for evaluating the presence of a syndemic. Our research begins by establishing a normative baseline mortality (BM) through life table analysis, where changes in life expectancy (LE) around BM can be used to show a distinctive pattern of significant decline and increase. Such was the case with the presence of both cholera and smallpox in the fall of 1865, when LE fell significantly to 19.64 years from the background LE of 32.88 years. A year later, this decline was followed by a significant increase in LE to 41.34 years. Excessive mortality followed by a fallow (healthy) period represents a signature feature of a syndemic driven by a short-term infectious disease epidemic. The presence of both cholera and smallpox in 1860 did not produce similar results, evidence which suggests that the presence of two infectious epidemics in an impoverished population was not sufficient to produce a syndemic. The presence of a protracted state of quarantine, with its concomitant social and economic consequences, was a driving force responsible for amplifying the disease burden in 1865, and elevating to a syndemic status. Multivariate Poisson regression revealed patio level limiting factors (such as, presence of a cistern, a well, a live-in servant, and a Jewish co-resident), as well as risk factors (such as, a smallpox death in the building; the presence of a foreign-born individual). From the two-phase assessment of the syndemic in Gibraltar, we developed a conceptual framework for identifying, contributing, driving, and limiting factors. •The 1865 Gibraltar cholera syndemic displayed features of the harvesting effect.•Driving syndemic factors were cholera and smallpox deaths, and quarantine.•Contributing factors were overcrowding, poor sanitation, and the daily influx of transients.•Poor relief was a limiting factor in the syndemic.•Patio-level limiting factors were, cistern, well, servant, and Jewish co-resident.