Background Food security has deteriorated for many people in developing regions facing high and volatile food prices. Without effective and equitable responses, the situation is likely to worsen due to diminishing access to land and water, competition from non-food uses of agricultural products, and the effects of climate change and variability. Understanding how this will affect the burden and distribution of major diseases such as HIV is critical. This study makes use of the near-experimental conditions created by the Malawi famine to shed new light on this issue. Methods Multilevel, random intercept models were used to relate the change in HIV prevalence at antenatal surveillance sites over the course of the famine to the proportion of rural households requiring food aid in the surrounding district at the famine’s peak. Similar models were used to relate this indicator of rural hunger to changes in the composition of the antenatal population. The extent and direction of migration were estimated from a household survey conducted 1–2 years after the famine. Findings At rural sites, the change in HIV prevalence was positively and non-linearly related to the extent of rural hunger (P = 0.016), consistent with contemporary accounts of increased transactional sex and with hunger compromising immune function. At non-rural sites, prevalence declined as rural hunger increased (P = 0.006), concentrated in women who self-identified as farmers (P = 0.010). This finding is consistent with contemporary accounts of migration in search of food and work from villages where HIV risk was lower to towns and cities where it was higher. Corroborating this interpretation, the proportion of farmers in the antenatal population was found to rise at non-rural sites as rural hunger increased in the surrounding district (P = 0.015) whereas the proportion fell with increasing rural hunger at rural sites (P<0.001). The models suggest migrants were predominantly farming women under 25 years (P = 0.010). The household survey confirmed that there was a surge of rural-to-urban migration during the famine, particularly by women under 25 years. Migration to less affected rural areas also increased. Conclusion The Malawi famine appears to have had a substantial effect on HIV’s dynamics and demography. Poverty and inequality, commonly considered structural determinants of HIV epidemics, can change rapidly, apparently transmitting their effects with little lag. Epidemic patterns risk being misread if such social and economic change is ignored. Many studies examining HIV prevalence declines have implicated sexual behaviour change but do not appear to have adequately considered the contribution of rural-urban migration. The evidence from Malawi, which links actions that undermined people’s food security to changes in the prevalence and distribution of HIV infections, suggests new opportunities for prevention.