We investigated the effects of non-insulin-dependent diabetes mellitus (NIDDM) on lipoprotein(a) (Lp[a]) and apolipoprotein(a) (apo[a]) in a population of Mexican-Americans. In plasma samples from 536 subjects, we measured Lp(a) concentrations, and we estimated apo(a) isoform sizes following immunostaining of plasma proteins resolved using sodium dodecyl sulfate electrophoresis. We identified 81 diabetic subjects who had 108 distinct apo(a) isoform bands. We then identified 81 nondiabetic subjects from the remainder who were closely matched for apo(a) phenotype (i.e., number and size of apo(a) isoform bands). As expected, the diabetic group had higher levels of glucose and insulin (both fasted and 2 h after glucose challenge) and triglycerides, and lower levels of high-density lipoprotein (HDL) cholesterol when compared with the matching nondiabetic group. Moreover, the diabetic group also had significantly lower Lp(a) concentrations than the nondiabetic subjects (10.6 vs. 13.6 mg/dl, P = 0.045) using a paired Student's t test. To detect the effects of diabetes on apo(a) size, we identified by pedigree analysis the nondiabetic family members who possessed alleles identical to those in the diabetic group. When we compared the average sizes for each allele, we found that apo(a) isoforms averaged 4.1 kDa larger in diabetic subjects than the genetically identical apo(a) measured in nondiabetic subjects (P = 0.044, n = 36 alleles). In summary, we have detected significant effects of NIDDM both on Lp(a) concentrations and on apo(a) size.