In light of the increasing availability of generic highly active antiretroviral therapy (HAART) in India, further data are needed to examine variables associated with HAART nonadherence among HIV-infected Indians in clinical care. We conducted a cross-sectional analysis of 198 HIV-infected South Indian men and women between January and April 2008 receiving first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART. Nonadherence was defined as taking less than 95% of HAART doses in the last 1 month, and was examined using multivariable logistic regression models. Half of the participants reported less than 95% adherence to HAART, and 50% had been on HAART for more than 24 months. The median CD4 cell count was 435 cells per microliter. An increased odds of nonadherence was found for participants with current CD4 cell counts greater than 500 cells per microliter (adjusted odds ratio [AOR]: 2.22 [95% confidence interval {CI}: 1.04–4.75]; p = 0.038), who were on HAART for more than 24 months (AOR: 3.07 [95% CI: 1.35–7.01]; p = 0.007), who reported alcohol use (AOR: 5.68 [95%CI: 2.10-15.32]; p = 0.001), who had low general health perceptions (AOR: 3.58 [95%CI: 1.20-10.66]; p = 0.021), and who had high distress (AOR: 3.32 [95%CI: 1.19-9.26]; p = 0.022). This study documents several modifiable risk factors for nonadherence in a clinic population of HIV-infected Indians with substantial HAART experience. Further targeted culturally specific interventions are needed that address barriers to optimal adherence.