Background Assessment of the functioning of Kerala’s second-line component of antiretroviral therapy (ART) program by National AIDS Control Organization (NACO) is attempted. Aims This study aims to evaluate the factors related to mortality and loss to follow-up (LFU) during the second-line ART rollout in Kerala. Materials and Methods Prospective observational cohort study. All patients referred for the second-line ART from September 2011 to June 2013 were included, followed up till December 2013 or till death. Those who were not eligible to attend the State AIDS Clinical Expert Panel (SACEP) were excluded from the study. Descriptive variables were compared using proportions and percentages. Univariate analysis and multivariate logistic regression were done to find out the association. The study was approved by ethical committee and consent was taken from all the interviewed patients. Results Of 238 patients enrolled, 62 died and 25 became LFU. Age >40 years (odds ratio [OR] 2.08; 95% confidence interval [CI]: 1.05, 4.1), HIV concordance between partners (OR 1.53; 95% CI: 0.7, 3.34), and duration of >90 days from last CD4+ to SACEP (OR 2.32; 95% CI: 1.17, 4.5) were significantly associated with death. Only factor affecting LFU was distance >150 km from patient’s home to ART Plus Centre (OR: 2.7; 95% CI: 0.11, 1.85). Limitations We could not consider all factors affecting mortality while initiating second-line ART. Moreover, experience from a low-level epidemic state, with good health-care infrastructure may not reflect rest of India. Conclusions Accessibility to program in terms of distance to the point of care and delayed linkage of patients for the second-line ART is presently the main weaknesses in Kerala. Special attention should be given to concordant couples and older individuals who are more vulnerable. Recent steps by NACO, such as initiation of two ART Plus Centre and provision viral load testing at the point of care, are big leaps toward solution.