Objective: Laboratory monitoring is recommended during combination antiretroviral therapy (cART), but the pattern of detected abnormalities and optimal monitoring are unknown. We assessed laboratory abnormalities during initial cART in 2000-2010 across the United States. Design: Observational study in the Centers for AIDS Research Network of Integrated Clinical Systems Cohort. Methods: Among patients with normal results within a year prior to cART initiation, time to first significant abnormality was assessed by Kaplan-Meier curves stratified by event type, with censoring at first of regimen change, loss to follow-up, or 104 weeks. Incidence rates of first events were estimated using Poisson regression; multivariable analyses identified associated factors. Results were stratified by time (16 weeks) from therapy initiation. Results: A total of 3470 individuals contributed 3639 person-years. Median age, pre-cART CD4, and follow-up duration were 40 years, 206 cells/μl, and 51 weeks, respectively. Incidence rates for significant abnormalities (per 100 person-years) in the first 16 weeks post-cART initiation were as follows: lipid = 49 [95% confidence interval (CI) 41 - 58]; hematologic = 44 (40-49); hepatic = 24 (20-27); and renal = 9 (7-11), dropping substantially during weeks 17-104 of cART to lipid = 23 (18-29); hematologic = 5 (4-6); hepatic = 6 (5-8); and renal = 2 (1-3) (all P<0.05). Among patients receiving initial cART with no prior abnormality (N= 1889), strongest associations for hepatic abnormalities after 16 weeks were hepatitis B and C [hazard ratio = 2.3 (95% CI 1.2-4.5) and hazard ratio=3.0 (1.9-4.5), respectively]. The strongest association for renal abnormalities was hypertension [hazard ratio = 2.8 (1.4-5.6)]. Conclusion: New abnormalities decreased after week 16 of cART. For abnormalities not present by week 16, subsequent monitoring should be guided by comorbidities.