Background: Few studies have assessed the determinants of birthweight in newborns from HIV-positive mothers in analyses that adjusted for different gestational age at delivery. Method: We calculated gestational age-adjusted birthweightZ-score values in a national series of 600 newborns from women with HIV and in 600 newborns from HIV-negative women matched for gender and gestational age. The determinants of Z-score values in newborns from HIV-positive mothers were assessed in univariate and multivariate regression analyses. Results: Compared to newborns from HIV-negative women, newborns from HIV-positive women had significantly lower absolute birthweight (2799 vs. 2887 g;p=.007) and birthweightZscore (-0.430 vs. -0.222; p 10 cigarettes/day (ZSD 0.323, 95% CI 0.129-0.518, p=.001), absence of pregnancies in the past (ZSD 0.200, 95% CI 0.050-0.349, p=.009), no antiretroviral treatment in the past (ZSD 0.186, 95% CI 0.044-0.327, p=.010), and Caucasian ethnicity compared to Hispanic (ZSD 0.248, 95% CI 0.022-0.475, p=.032). Body mass index (BMI) at conception and maternal glycemia levels during pregnancy were also significantly related to birthweight Z scores. Glycemia, BMI, and recent substance use maintained a significant association with Z-score values in multivariate analyses. In the multivariate analysis, the only factors significantly associated with Z-score values below the 10th percentile were recent substance use (adjusted odds ratio [AOR] 3.17, 95% CI 1.15-8.74) and smoking (AOR 2.26, 95% CI 1.13-4.49). Discussion: We identified several factors associated with gestational age-adjusted birthweight in newborns from women with HIV Smoking and substance use have a significant negative impact on intrauterine growth, which adds to an independent HIV-related effect on birthweight. Prevention and information on this issue should be reinforced in women with HIV of childbearing age to reduce the risk of negative outcomes in their offspring.