BACKGROUND: Since 2001 the South African guidelines to improve child health and prevent vertical HIV transmission recommended frequent infant follow-up with HIV testing at 18 months postpartum. We sought to understand non-attendance at scheduled follow-up study visits up to 18 months, and for the 18-month infant HIV test amongst a nationally representative sample of HIV exposed uninfected (HEU) infants from a high HIV-prevalence African setting. METHODS: Secondary analysis of data drawn from a nationally representative observational cohort study (conducted during October 2012 to September 2014) of HEU infants and their primary caregivers was undertaken. Participants were eligible (N = 2650) if they were 4-8 weeks old and HEU at enrolment. All enrolled infants were followed up every 3 months up to 18 months. Each follow-up visit was scheduled to coincide with each child's routine health visit, where possible. The denominator at each time point comprised HEU infants who were alive and HIV-free at the previous visit. We assessed baseline maternal and early HIV care characteristics associated with the frequency of 'Missed visits' (MV-frequency), using a negative binomial regression model adjusting for the follow-up time in the study, and associated with missed visits at 18 months (18-month MV) using a logistic regression model. RESULTS: The proportion of eligible infants with MV was lowest at 3 months (32.7%) and 18 months (31.0%) and highest at 12 months (37.6%). HIV-positive mothers not on triple antiretroviral therapy (ART) by 6-weeks postpartum had a significantly increased occurrence rate of 'MV-frequency' (adjusted incidence rate ratio, 1.2 (95% confidence interval (CI), 1.1-1.4), p < 0.0001). Compared to those mothers with ART, these mothers also increased the risk of '18-month-MV' (adjusted odds ratio, 1.3 (CI, 1.1-1.6), p = 0.006). Unknown infant nevirapine-intake status increased the rate of 'MV-frequency' (p = 0.02). Mothers > 24 years had a significantly reduced rate of 'MV-frequency' (p ≤ 0.01) and risk of '18-month-MV' (p < 0.01) compared to younger women. Shorter travel time to health facility lowered the occurrence of 'MV-frequency' (p ≤ 0.004). CONCLUSION: Late initiation of maternal ART and infant prophylaxis under the Option- A policy and extended travel time to clinics (measured at 6 weeks postpartum), contributed to higher postnatal MV rates. Mothers older than 24 years had lower MV rates. Targeted interventions may be needed during the current PMTCT Option B+ (lifelong ART to pregnant and lactating women at HIV diagnosis) to circumvent these risk factors and reduce missed visits during HIV-care.