The proximal femur MLD 46 (Australopithecus africanus) from Makapansgat, South Africa, shows extensive osteophyte formation at the head-neck junction. These pathological alterations are responsible for neglecting MLD 46 in most studies on the postcranium of A. africanus. Here, we compare its morphology to a modern sample from the Galler collection with known pathologies to establish a differential diagnosis. We found that primary osteoarthritis is most similar to the morphology of MLD 46. The differential diagnosis includes pathologies like a protrusion of the acetabulum, congenital or acquired coxa vara and femoroacetabular impingement syndrome, which led to secondary osteoarthritis. Australopithecus may have had some predisposition for coxa vara and impingement syndrome due to the slightly different morphology of the proximal femur compared to modern humans. Possible, but less likely differential diagnoses include rheumatoid arthritis and Paget’s disease. As primary osteoarthritis is age related, this disorder may be an indication of an advanced individual age of MLD 46. This would suggest that MLD 46 is one of the oldest australopithecine individuals discovered so far.