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It is widely appreciated that ozone-depleting substances (ODS), which have led to the formation of the Antarctic ozone hole, are also powerful greenhouse gases. In this study, we explore the consequence of the surface warming caused by ODS in the second half of the twentieth century over the Indo-Pacific Ocean, using the Whole Atmosphere Chemistry Climate Model (version 4). By contrasting two ensembles of chemistry-climate model integrations (with and without ODS forcing) over the period 1955-2005, we show that the additional greenhouse effect of ODS is crucial to producing a statistically significant weakening of the Walker circulation in our model over that period. When ODS concentrations are held fixed at 1955 levels, the forcing of the other well-mixed greenhouse gases alone leads to a strengthening-rather than weakening-of the Walker circulation because their warming effect is not sufficiently strong. Without increasing ODS, a surface warming delay in the eastern tropical Pacific Ocean leads to an increase in the sea surface temperature gradient between the eastern and western Pacific, with an associated strengthening of the Walker circulation. When increasing ODS are added, the considerably larger total radiative forcing produces a much faster warming in the eastern Pacific, causing the sign of the trend to reverse and the Walker circulation to weaken. Our modeling result suggests that ODS may have been key players in the observed weakening of the Walker circulation over the second half of the twentieth century.