Background: The HIV care cascade has improved in Latin America over the last decade. However, the influence of alcohol and noninjected drug use (NIDU) on cascade outcomes is mostly unknown. This study estimated the association of alcohol and NIDU with retention in care, loss to follow up (LTFU), and virologic failure (VF). Methods: Individuals ≥18 years attending routine HIV clinic visits and completing the Rapid Screening Tool (RST; evaluating NIDU and ART adherence in 7-day recall period) during 2012–13 were followed up to 2015 in the Caribbean, Central and South America network for HIV epidemiology. Adjusted odds ratios (aOR) were calculated for the association of alcohol consumption and NIDU with retention in care by logistic regression; adjusted hazard ratios (aHR) were estimated for the associations with LTFU and VF by Cox regression. Results: Among 3604 individuals, the proportions retained in care for one year were 84%, 79%, 72%, and 69% for patients reporting non-use, alcohol use, NIDU, and both alcohol and NIDU, respectively. For the same patient groups, the proportions LTFU over 18 months were 6%, 8%, 12%, and 13%, respectively. There were 1901 patients (53%) with HIV RNA results; VF proportions were similar between users and nonusers (ranging from 14–16%). After controlling for age, sex, study site, HIV transmission mode, time on ART, AIDS status, and CD4 count, neither alcohol use (aOR = 1.1, CI = 0.9–1.4; aHR = 1.0, CI = 0.8–1.3) nor NIDU (aOR = 1.3, CI = 0.9–1.8; aHR = 1.4, CI = 0.9–2.1) were significantly associated with retention or VF, respectively. However, both alcohol use (aHR = 1.2, CI = 1.02–1.4) and NIDU (aHR = 1.3, CI = 1.00–1.8) were associated with increased LTFU. Conclusion: Alcohol use and NIDU in a 7-day recall period increased the risk of being LTFU during the next 18 months, highlighting the need for routine screening and targeted interventions to keep these individuals in care and on ART.