Men’s increased risk of death in ART programmes in sub-Saharan Africa is widely reported but poorly understood. Some studies have attributed this risk to men’s poorer health-seeking behaviour, which may prevent them from accessing ART, being adherent to treatment, or remaining in care. In a multicentre analysis of 46 201 adults starting ART in urban and rural settings in South Africa, these factors only partly explained men’s increased mortality while receiving ART. Importantly, the gender difference in mortality among patients receiving ART (31% higher for men than women) was substantially smaller than that among HIV negative South Africans, where men had twice the risk of death compared with women. Yet, this extreme gender inequality in mortality, both within and outside of ART programmes, has not given rise to widespread action. Here it is argued that, despite their dominance in society, men may be subject to a wide range of unfair discriminatory practices, which negatively affect their health outcomes. The health needs of men and boys require urgent attention.